FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3168889671> ?p ?o ?g. }

• W3168889671 endingPage "860" @default.
• W3168889671 startingPage "848" @default.
• W3168889671 abstract "Both severe acute respiratory syndrome virus 2 (SARS-CoV-2) and SARS-CoV mainly invade human lungs, although increasing evidence shows that SARS-CoV-2 can also infect many other tissues to develop systematic infection and multiple organ damage, and can also hijack T cells to directly paralyze host immunity.Angiotensin-converting enzyme 2 (ACE2) is the major receptor for SARS-CoV-2 infection and is a crucial determinant for cross-species transmission of the virus; SARS-CoV-2 can establish infections in a panel of domestic or wild animals via their ACE2 orthologs.Several proteins and non-protein molecules have been found to interact with SARS-CoV-2 S protein and serve as potential alternative/auxiliary attachment receptors/coreceptors to facilitate SARS-CoV-2 entry into specific types of host cells.Membrane fusion of SARS-CoV-2 requires two proteolytic events of S protein by host proteases, and the S1/S2 boundary of SARS-CoV-2 S protein harbors a polybasic insertion that expands the spectrum of available proteases and thus the tropism for different tissues. Severe acute respiratory syndrome virus 2 (SARS-CoV-2) invades host cells by interacting with receptors/coreceptors, as well as with other cofactors, via its spike (S) protein that further mediates fusion between viral and cellular membranes. The host membrane protein, angiotensin-converting enzyme 2 (ACE2), is the major receptor for SARS-CoV-2 and is a crucial determinant for cross-species transmission. In addition, some auxiliary receptors and cofactors are also involved that expand the host/tissue tropism of SARS-CoV-2. After receptor engagement, specific proteases are required that cleave the S protein and trigger its fusogenic activity. Here we discuss the recent advances in understanding the molecular events during SARS-CoV-2 entry which will contribute to developing vaccines and therapeutics. Severe acute respiratory syndrome virus 2 (SARS-CoV-2) invades host cells by interacting with receptors/coreceptors, as well as with other cofactors, via its spike (S) protein that further mediates fusion between viral and cellular membranes. The host membrane protein, angiotensin-converting enzyme 2 (ACE2), is the major receptor for SARS-CoV-2 and is a crucial determinant for cross-species transmission. In addition, some auxiliary receptors and cofactors are also involved that expand the host/tissue tropism of SARS-CoV-2. After receptor engagement, specific proteases are required that cleave the S protein and trigger its fusogenic activity. Here we discuss the recent advances in understanding the molecular events during SARS-CoV-2 entry which will contribute to developing vaccines and therapeutics. In late 2019 a novel coronavirus named SARS-CoV-2 emerged in humans, that causes coronavirus disease 2019 (COVID-19) [1.Coronaviridae Study Group of the International Committee on Taxonomy of Viruses The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2.Nat. Microbiol. 2020; 5: 536-544Crossref PubMed Scopus (2460) Google Scholar, 2.Zhou P. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (7642) Google Scholar, 3.Zhu N. et al.A novel coronavirus from patients with pneumonia in China, 2019.New Engl. J. Med. 2020; 382: 727-733Crossref PubMed Scopus (9884) Google Scholar, 4.Wu F. et al.A new coronavirus associated with human respiratory disease in China.Nature. 2020; 579: 265-269Crossref PubMed Scopus (3658) Google Scholar]. This outbreak has rapidly developed into a worldwide pandemic and has resulted in more than 0.1 billion confirmed cases as of 23 May 2021, including ~3.5 million deaths (www.who.int/emergencies/diseases/novel-coronavirus-2019). SARS-CoV-2 is the seventh human-infecting coronavirus (HCoV) identified so far (Box 1), and it is most similar to SARS-CoV which emerged in 2002 [4.Wu F. et al.A new coronavirus associated with human respiratory disease in China.Nature. 2020; 579: 265-269Crossref PubMed Scopus (3658) Google Scholar,5.Zhong N.S. et al.Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People's Republic of China, in February, 2003.Lancet. 2003; 362: 1353-1358Abstract Full Text Full Text PDF PubMed Scopus (732) Google Scholar]. However, SARS-CoV-2 exhibits a higher transmission efficiency (see Glossary) compared to SARS-CoV and other HCoVs [6.Madewell Z.J. et al.Household transmission of SARS-CoV-2: a systematic review and meta-analysis.JAMA Netw. Open. 2020; 3e2031756Crossref PubMed Scopus (86) Google Scholar], although it has a relatively lower mortality rate than SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) [6.Madewell Z.J. et al.Household transmission of SARS-CoV-2: a systematic review and meta-analysis.JAMA Netw. Open. 2020; 3e2031756Crossref PubMed Scopus (86) Google Scholar, 7.Liu Z. et al.The assessment of transmission efficiency and latent infection period in asymptomatic carriers of SARS-CoV-2 infection.Int. J. Infect. Dis. 2020; 99: 325-327Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 8.Zumla A. et al.Middle East respiratory syndrome.Lancet. 2015; 386: 995-1007Abstract Full Text Full Text PDF PubMed Scopus (589) Google Scholar]. Although several candidate vaccines are being distributed in different countries, the global pandemic situation is far from under control. It is very urgent to promote vaccination among human populations and to develop effective therapeutics.Box 1Coronaviruses and related epidemics/pandemicsCoronaviruses are a group of enveloped viruses whose surface is decorated with spike (S) proteins, resulting in a crown-shaped morphology. The genome of coronaviruses is a single-stranded positive-sense RNA that can directly serve as an mRNA for translation of viral proteins [11.V'Kovski P. et al.Coronavirus biology and replication: implications for SARS-CoV-2.Nat. Rev. Microbiol. 2020; 19: 155-170Crossref PubMed Scopus (0) Google Scholar]. Coronaviruses belong to the order of Nidovirales, the family Coronaviridae, and are further classified into Orthocoronavirinae and Letovirinae subfamilies. All human-infecting coronaviruses (HCoVs) are included in the subfamily Orthocoronavirinae, which are further divided into four genera, Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus [9.Siddell S.G. et al.Coronaviridae.Intervirology. 1983; 20: 181-189Crossref PubMed Scopus (55) Google Scholar]. So far, a total of seven HCoVs have been identified. Among them, the 229E, NL63, OC43, and HKU1 coronaviruses are commonly found in human populations around the world, resulting in mild symptoms such as common cold and fever. The other three, SARS-CoV, MERS-CoV, and SARS-CoV-2, are categorized as highly pathogenic coronaviruses which have caused epidemics/pandemics in different countries.The first identified HCoVs are 229E and OC43, reported in the 1960s (Figure I) [107.Tyrrell D.A. Bynoe M.L. Cultivation of a novel type of common-cold virus in organ cultures.Br. Med. J. 1965; 1: 1467-1470Crossref PubMed Google Scholar,108.Hamre D. Procknow J.J. A new virus isolated from the human respiratory tract.Proc. Soc. Exp. Biol. Med. 1966; 121: 190-193Crossref PubMed Google Scholar]. They are often detected at the same time as other respiratory infections and usually do not lead to severe symptoms. In 2004 the NL63 coronavirus was discovered in a baby with bronchiolitis in The Netherlands [109.van der Hoek L. et al.Identification of a new human coronavirus.Nat. Med. 2004; 10: 368-373Crossref PubMed Scopus (1155) Google Scholar]. A year later the HKU1 coronavirus was identified in Hong Kong, China from an elderly patient with pneumonia [110.Woo P.C. et al.Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia.J. Virol. 2005; 79: 884-895Crossref PubMed Scopus (920) Google Scholar]. Since then, this virus has been found in human populations around the world. The first case of SARS-CoV infection was found in Guangdong, China in late 2002 [5.Zhong N.S. et al.Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People's Republic of China, in February, 2003.Lancet. 2003; 362: 1353-1358Abstract Full Text Full Text PDF PubMed Scopus (732) Google Scholar]. The epidemic spread to over 30 countries and ended in 2003, resulting in more than 8000 reported cases of infection, including almost 800 deaths. MERS-CoV was first identified in Saudi Arabia in 2012 and has been found in many Middle East countries as well as in some Asian countries [111.Zaki A.M. et al.Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.New Engl. J. Med. 2012; 367: 1814-1820Crossref PubMed Scopus (2963) Google Scholar]. So far, more than 2500 confirmed infection cases have been reported, of which ~850 died from MERS-related disease, and thus has the highest case fatality rate (~35%) of all HCoVs. SARS-CoV-2 infection cases were first reported in Wuhan, China, in late 2019 [3.Zhu N. et al.A novel coronavirus from patients with pneumonia in China, 2019.New Engl. J. Med. 2020; 382: 727-733Crossref PubMed Scopus (9884) Google Scholar]. This virus has led to the unprecedented ongoing global pandemic that affects almost all countries around the world. As of 23 May 2021, more than 0.1 billion human infection cases have been confirmed, including almost 3.5 million death cases. The case fatality rate of SARS-CoV-2 is much lower than those of SARS-CoV and MERS-CoV, but it seems to be more efficient in transmission among human populations. All three highly pathogenic HCoVs are thought to originate from wild animals, potentially with a common natural host, bats [2.Zhou P. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (7642) Google Scholar,112.Hu B. et al.Bat origin of human coronaviruses.Virol. J. 2015; 12: 221Crossref PubMed Scopus (181) Google Scholar]. Coronaviruses are a group of enveloped viruses whose surface is decorated with spike (S) proteins, resulting in a crown-shaped morphology. The genome of coronaviruses is a single-stranded positive-sense RNA that can directly serve as an mRNA for translation of viral proteins [11.V'Kovski P. et al.Coronavirus biology and replication: implications for SARS-CoV-2.Nat. Rev. Microbiol. 2020; 19: 155-170Crossref PubMed Scopus (0) Google Scholar]. Coronaviruses belong to the order of Nidovirales, the family Coronaviridae, and are further classified into Orthocoronavirinae and Letovirinae subfamilies. All human-infecting coronaviruses (HCoVs) are included in the subfamily Orthocoronavirinae, which are further divided into four genera, Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus [9.Siddell S.G. et al.Coronaviridae.Intervirology. 1983; 20: 181-189Crossref PubMed Scopus (55) Google Scholar]. So far, a total of seven HCoVs have been identified. Among them, the 229E, NL63, OC43, and HKU1 coronaviruses are commonly found in human populations around the world, resulting in mild symptoms such as common cold and fever. The other three, SARS-CoV, MERS-CoV, and SARS-CoV-2, are categorized as highly pathogenic coronaviruses which have caused epidemics/pandemics in different countries. The first identified HCoVs are 229E and OC43, reported in the 1960s (Figure I) [107.Tyrrell D.A. Bynoe M.L. Cultivation of a novel type of common-cold virus in organ cultures.Br. Med. J. 1965; 1: 1467-1470Crossref PubMed Google Scholar,108.Hamre D. Procknow J.J. A new virus isolated from the human respiratory tract.Proc. Soc. Exp. Biol. Med. 1966; 121: 190-193Crossref PubMed Google Scholar]. They are often detected at the same time as other respiratory infections and usually do not lead to severe symptoms. In 2004 the NL63 coronavirus was discovered in a baby with bronchiolitis in The Netherlands [109.van der Hoek L. et al.Identification of a new human coronavirus.Nat. Med. 2004; 10: 368-373Crossref PubMed Scopus (1155) Google Scholar]. A year later the HKU1 coronavirus was identified in Hong Kong, China from an elderly patient with pneumonia [110.Woo P.C. et al.Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia.J. Virol. 2005; 79: 884-895Crossref PubMed Scopus (920) Google Scholar]. Since then, this virus has been found in human populations around the world. The first case of SARS-CoV infection was found in Guangdong, China in late 2002 [5.Zhong N.S. et al.Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People's Republic of China, in February, 2003.Lancet. 2003; 362: 1353-1358Abstract Full Text Full Text PDF PubMed Scopus (732) Google Scholar]. The epidemic spread to over 30 countries and ended in 2003, resulting in more than 8000 reported cases of infection, including almost 800 deaths. MERS-CoV was first identified in Saudi Arabia in 2012 and has been found in many Middle East countries as well as in some Asian countries [111.Zaki A.M. et al.Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.New Engl. J. Med. 2012; 367: 1814-1820Crossref PubMed Scopus (2963) Google Scholar]. So far, more than 2500 confirmed infection cases have been reported, of which ~850 died from MERS-related disease, and thus has the highest case fatality rate (~35%) of all HCoVs. SARS-CoV-2 infection cases were first reported in Wuhan, China, in late 2019 [3.Zhu N. et al.A novel coronavirus from patients with pneumonia in China, 2019.New Engl. J. Med. 2020; 382: 727-733Crossref PubMed Scopus (9884) Google Scholar]. This virus has led to the unprecedented ongoing global pandemic that affects almost all countries around the world. As of 23 May 2021, more than 0.1 billion human infection cases have been confirmed, including almost 3.5 million death cases. The case fatality rate of SARS-CoV-2 is much lower than those of SARS-CoV and MERS-CoV, but it seems to be more efficient in transmission among human populations. All three highly pathogenic HCoVs are thought to originate from wild animals, potentially with a common natural host, bats [2.Zhou P. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (7642) Google Scholar,112.Hu B. et al.Bat origin of human coronaviruses.Virol. J. 2015; 12: 221Crossref PubMed Scopus (181) Google Scholar]. SARS-CoV-2 is a positive-sense RNA virus with a large single-stranded RNA genome of ~30 000 nt [9.Siddell S.G. et al.Coronaviridae.Intervirology. 1983; 20: 181-189Crossref PubMed Scopus (55) Google Scholar]. The genome encodes three classes of proteins: two large polyproteins, pp1a and pp1ab, which are cleaved into 16 non-structural proteins (NSPs) that are required for viral RNA synthesis (and probably other functions); four structural proteins (the spike, envelope, membrane, and nucleocapsid proteins) that are essential for viral entry and assembly; and nine accessory proteins that are thought to counteract the host immunity during infection [10.Fehr A.R. Perlman S. Coronaviruses: an overview of their replication and pathogenesis.Methods Mol. Biol. 2015; 1282: 1-23Crossref PubMed Google Scholar,11.V'Kovski P. et al.Coronavirus biology and replication: implications for SARS-CoV-2.Nat. Rev. Microbiol. 2020; 19: 155-170Crossref PubMed Scopus (0) Google Scholar]. Viral entry is the first step of infection and one of the most important processes in the virus life cycle, which is also the key target for vaccines and therapeutics. This process is executed by the S protein on the envelope of SARS-CoV-2, which recognizes the host cell receptor and mediates membrane fusion to allow the viral genome to be released into the cytoplasm [12.Belouzard S. et al.Mechanisms of coronavirus cell entry mediated by the viral spike protein.Viruses. 2012; 4: 1011-1033Crossref PubMed Google Scholar]. In this review, we summarize the recent functional and structural studies on SARS-CoV-2 entry, with an emphasis on the S protein-mediated receptor binding and membrane fusion processes, as well as on other cellular factors and coreceptors that are potentially involved in the viral entry process (Figure 1). An average of 30–60 S protein trimers protrude from the envelope of SARS-CoV-2 virion, with an average distance of 15 nm from each other [13.Yao H. et al.Molecular architecture of the SARS-CoV-2 virus.Cell. 2020; 183: 730-738Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 14.Ke Z. et al.Structures and distributions of SARS-CoV-2 spike proteins on intact virions.Nature. 2020; 588: 498-502Crossref PubMed Scopus (170) Google Scholar, 15.Turonova B. et al.In situ structural analysis of SARS-CoV-2 spike reveals flexibility mediated by three hinges.Science. 2020; 370: 203-208Crossref PubMed Scopus (135) Google Scholar]. Each trimeric spike is ~10 nm in length with a long helix stalk hinge that allows the spike to adopt different orientations on the viral envelope [14.Ke Z. et al.Structures and distributions of SARS-CoV-2 spike proteins on intact virions.Nature. 2020; 588: 498-502Crossref PubMed Scopus (170) Google Scholar,15.Turonova B. et al.In situ structural analysis of SARS-CoV-2 spike reveals flexibility mediated by three hinges.Science. 2020; 370: 203-208Crossref PubMed Scopus (135) Google Scholar]. The coronavirus S protein is a typical class I viral fusion protein and is the largest viral fusion machine identified so far, containing more than 1200 amino acid residues. During the cell entry process, the SARS-CoV-2 S protein undergoes proteolytic cleavage by cellular proteases into the S1 and S2 subunits which remain associated and further assemble into trimers of the S1/S2 heterodimer (Figure 2) [16.Duan L. et al.The SARS-CoV-2 spike glycoprotein biosynthesis, structure, function, and antigenicity: implications for the design of spike-based vaccine immunogens.Front. Immunol. 2020; 11576622Crossref PubMed Scopus (46) Google Scholar,17.Walls A.C. et al.Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein.Cell. 2020; 181: 281-292Abstract Full Text Full Text PDF PubMed Scopus (2842) Google Scholar]. The S1 subunit can be divided into the N-terminal domain (NTD) and the C-terminal domain (CTD), of which the latter is responsible for binding the host receptor angiotensin-converting enzyme 2 (ACE2) and is thus also termed the receptor-binding domain (RBD) [17.Walls A.C. et al.Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein.Cell. 2020; 181: 281-292Abstract Full Text Full Text PDF PubMed Scopus (2842) Google Scholar, 18.Wrapp D. et al.Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.Science. 2020; 367: 1260-1263Crossref PubMed Scopus (19) Google Scholar, 19.Wang Q.H. et al.Structural and functional basis of SARS-CoV-2 entry by using human ACE2.Cell. 2020; 181: 894-904Abstract Full Text Full Text PDF PubMed Scopus (890) Google Scholar, 20.Lan J. et al.Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.Nature. 2020; 581: 215-220Crossref PubMed Scopus (1531) Google Scholar, 21.Shang J. et al.Structural basis of receptor recognition by SARS-CoV-2.Nature. 2020; 581: 221-224Crossref PubMed Scopus (1165) Google Scholar]. The S2 subunit is the fusogenic portion of the spike and consists of the upstream helix (UH) region, the fusion peptide (FP), the heptad repeat 1 (HR1), the central domain (CD), the heptad repeat 2 (HR2), the transmembrane domain (TM), and the cytoplasmic tail (CP) (Figure 2A,B). In contrast to most typical class I viral fusion proteins, the FP of coronavirus S protein is not located at the immediate N terminus of the S2 subunit. Instead, it is shielded by the UH domain which therefore requires a second cleavage event to expose the FP [22.Matsuyama S. Protease-dependent cell entry mechanism of coronaviruses.Uirusu. 2011; 61 (article in Japanese): 109-116Crossref PubMed Scopus (1) Google Scholar,23.Walls A.C. et al.Tectonic conformational changes of a coronavirus spike glycoprotein promote membrane fusion.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 11157-11162Crossref PubMed Scopus (218) Google Scholar]. Proteolysis at the S2′ cleavage site to remove the UH domain is crucial for activating the fusogenic capacity of S protein, and triggers irreversible conformational changes of the S2 fusion machine to initiate membrane fusion [24.Fan X. et al.Cryo-EM analysis of the post-fusion structure of the SARS-CoV spike glycoprotein.Nat. Commun. 2020; 11: 3618Crossref PubMed Scopus (41) Google Scholar, 25.Hoffmann M. et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280Abstract Full Text Full Text PDF PubMed Scopus (6278) Google Scholar, 26.Cai Y. et al.Distinct conformational states of SARS-CoV-2 spike protein.Science. 2020; 369: 1586-1592Crossref PubMed Scopus (207) Google Scholar]. Soon after the outbreak, several groups promptly identified ACE2 as the major receptor for SARS-CoV-2, similar to SARS-CoV that emerged in 2002–2003 [2.Zhou P. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (7642) Google Scholar,17.Walls A.C. et al.Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein.Cell. 2020; 181: 281-292Abstract Full Text Full Text PDF PubMed Scopus (2842) Google Scholar,25.Hoffmann M. et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280Abstract Full Text Full Text PDF PubMed Scopus (6278) Google Scholar] (Figure 3). ACE2, a carboxypeptidase that cleaves polypeptides from the renin/angiotensin system, is essential for cardiac function and is widely expressed in various tissues and organs, suggesting the potential capacity of SARS-CoV-2 to develop systematic infections in patients [27.Kuba K. et al.Multiple functions of angiotensin-converting enzyme 2 and its relevance in cardiovascular diseases.Circ. J. 2013; 77: 301-308Crossref PubMed Scopus (96) Google Scholar,28.Yan R. et al.Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2.Science. 2020; 367: 1444-1448Crossref PubMed Scopus (1720) Google Scholar]. The RBDs of SARS-CoV-2 and SARS-CoV share a high degree of sequence identity (74%) and exhibit highly similar interaction profiles with ACE2 [19.Wang Q.H. et al.Structural and functional basis of SARS-CoV-2 entry by using human ACE2.Cell. 2020; 181: 894-904Abstract Full Text Full Text PDF PubMed Scopus (890) Google Scholar, 20.Lan J. et al.Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.Nature. 2020; 581: 215-220Crossref PubMed Scopus (1531) Google Scholar, 21.Shang J. et al.Structural basis of receptor recognition by SARS-CoV-2.Nature. 2020; 581: 221-224Crossref PubMed Scopus (1165) Google Scholar]. However, some substitutions in the key interacting residues in the RBD lead to more atomic contacts between SARS-CoV-2 S protein and ACE2, potentially resulting in the higher binding affinity compared to SARS-CoV (~fourfold difference) (Figure 3C,D) [19.Wang Q.H. et al.Structural and functional basis of SARS-CoV-2 entry by using human ACE2.Cell. 2020; 181: 894-904Abstract Full Text Full Text PDF PubMed Scopus (890) Google Scholar]. This property may contribute to the highly efficient human-to-human transmission of SARS-CoV-2 [6.Madewell Z.J. et al.Household transmission of SARS-CoV-2: a systematic review and meta-analysis.JAMA Netw. Open. 2020; 3e2031756Crossref PubMed Scopus (86) Google Scholar,7.Liu Z. et al.The assessment of transmission efficiency and latent infection period in asymptomatic carriers of SARS-CoV-2 infection.Int. J. Infect. Dis. 2020; 99: 325-327Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar]. In addition, ACE2 orthologs are widely distributed in various domestic and wild mammals such as cats, dogs, pigs, camels, horses, pangolins, and bats, indicating that SARS-CoV2 is likely to have a broad host spectrum [29.Rodrigues J. et al.Insights on cross-species transmission of SARS-CoV-2 from structural modeling.PLoS Comput. Biol. 2020; 16e1008449Crossref PubMed Scopus (5) Google Scholar]. Some closely related coronaviruses to SARS-CoV-2 have been isolated in pangolins and bats [2.Zhou P. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (7642) Google Scholar,30.Xiao K.P. et al.Isolation of SARS-CoV-2-related coronavirus from Malayan pangolins.Nature. 2020; 583: 286-289Crossref PubMed Scopus (208) Google Scholar]. Two recent studies have shown that the ACE2 orthologs of a wide range of animals can bind SARS-CoV-2 RBD and mediate the cell entry of S pseudotyped viruses, although the S-binding interface displays significant diversity (Figure 3E,F) [31.Liu K. et al.Cross-species recognition of SARS-CoV-2 to bat ACE2.Proc. Natl. Acad. Sci. U. S. A. 2021; 118e2020216118Crossref PubMed Scopus (2) Google Scholar,32.Wu L. et al.Broad host range of SARS-CoV-2 and the molecular basis for SARS-CoV-2 binding to cat ACE2.Cell Discov. 2020; 6: 68Crossref PubMed Scopus (26) Google Scholar]. These findings strongly imply that SARS-CoV-2 may have experienced multiple spillover events in adaptation to the diverse molecular determinants in different animals, which enabled its host-jump across different intermediate hosts and finally allowed it to infect humans. Cryogenic electron microscopy (cryo-EM) studies have determined the structures of SARS-CoV-2 S protein in various conformations, both before and after membrane fusion [17.Walls A.C. et al.Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein.Cell. 2020; 181: 281-292Abstract Full Text Full Text PDF PubMed Scopus (2842) Google Scholar,18.Wrapp D. et al.Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.Science. 2020; 367: 1260-1263Crossref PubMed Scopus (19) Google Scholar,26.Cai Y. et al.Distinct conformational states of SARS-CoV-2 spike protein.Science. 2020; 369: 1586-1592Crossref PubMed Scopus (207) Google Scholar], as well as its complex with the receptor ACE2 [33.Benton D.J. et al.Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion.Nature. 2020; 588: 327-330Crossref PubMed Scopus (119) Google Scholar, 34.Xu C. et al.Conformational dynamics of SARS-CoV-2 trimeric spike glycoprotein in complex with receptor ACE2 revealed by cryo-EM.Sci. Adv. 2020; 7eabe5575Crossref Scopus (17) Google Scholar, 35.Zhou T.Q. et al.Cryo-EM structures of SARS-CoV-2 spike without and with ACE2 reveal a pH-dependent switch to mediate endosomal positioning of receptor-binding domains.Cell Host Microbe. 2020; 28: 867-879Abstract Full Text Full Text PDF PubMed Google Scholar]. These structural snapshots enable the deduction of a complete scenario for the conformational changes of S protein during SARS-CoV-2 entry (Figure 4). The RBD of S protein can adopt different conformations at the prefusion state in which the receptor binding interface is buried by the adjacent protomer (closed conformation) or exposed for the access by ACE2 (open conformation) (Figures 2C and 4A), similar to other known coronavirus S proteins [17.Walls A.C. et al.Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein.Cell. 2020; 181: 281-292Abstract Full Text Full Text PDF PubMed Scopus (2842) Google Scholar,18.Wrapp D. et al.Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.Science. 2020; 367: 1260-1263Crossref PubMed Scopus (19) Google Scholar,36.Yuan Y. et al.Cryo-EM structures of MERS-CoV and SARS-CoV spike glycoproteins reveal the dynamic receptor binding domains.Nat. Commun. 2017; 8: 15092Crossref PubMed Scopus (342) Google Scholar]. The three RBDs within a trimeric spike are not synchronized, implying asymmetric interactions with the receptor. A recent study revealed that binding of ACE2 to an open RBD can promote the conformational transition of the other closed RBDs to make them accessible by the receptor (Figure 4B) [33.Benton D.J. et al.Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion.Nature. 2020; 588: 327-330Crossref PubMed Scopus (119) Google Scholar]. Therefore, a trimeric spike can bind to 1–3 copies of ACE2, depending on the conformation of each individual RBD [33.Benton D.J. et al.Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion.Nature. 2020; 588: 327-330Crossref PubMed Scopus (119) Google Scholar,35.Zhou T.Q. et al.Cryo-EM structures of SARS-CoV-2 spike without and with ACE2 reveal a pH-dependent switch to mediate endosomal positioning of receptor-binding domains.Cell Host Microbe. 2020; 28: 867-879Abstract Full Text Full Text PDF PubMed Google Scholar]. The binding of ACE2 modulates the local conformation of S1 subunit to disrupt its interactions with the S2 fusion core, which involves a key salt bridge contributed by residue D614 [33.Benton D.J. et al.Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion.Nature. 2020; 588: 327-330Crossref PubMed Scopus (119) Google Scholar]. Progressive interactions with ACE2 molecules will lead to dissociation of the S1 head from the fusogenic S2 stalk, which facilitates fusion activation by further proteolysis at the S2′ site (Figure 4C) [33.Benton D.J. et al.Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion.Nature. 2020; 588: 327-330Crossref PubMed Scopus (119) Google Scholar]. Of note, a SARS-CoV-2 variant harboring a D614G substitution in S protein was identified in Europe in mid-2020. This mutation makes the RB" @default.
• W3168889671 created "2021-06-22" @default.
• W3168889671 creator A5015873777 @default.
• W3168889671 creator A5027163111 @default.
• W3168889671 creator A5063079472 @default.
• W3168889671 creator A5064837815 @default.
• W3168889671 creator A5087385265 @default.
• W3168889671 date "2021-10-01" @default.
• W3168889671 modified "2023-10-12" @default.
• W3168889671 title "Cell entry by SARS-CoV-2" @default.
• W3168889671 cites W1489664555 @default.
• W3168889671 cites W1994573674 @default.
• W3168889671 cites W2006079378 @default.
• W3168889671 cites W2052319450 @default.
• W3168889671 cites W2055565790 @default.
• W3168889671 cites W2066918280 @default.
• W3168889671 cites W2092162071 @default.
• W3168889671 cites W2105149323 @default.
• W3168889671 cites W2111412754 @default.
• W3168889671 cites W2138324310 @default.
• W3168889671 cites W2141877163 @default.
• W3168889671 cites W2163242365 @default.
• W3168889671 cites W2166867592 @default.
• W3168889671 cites W2170933940 @default.
• W3168889671 cites W2200668708 @default.
• W3168889671 cites W2321725740 @default.
• W3168889671 cites W2332629841 @default.
• W3168889671 cites W2606148195 @default.
• W3168889671 cites W2755284350 @default.
• W3168889671 cites W2762161295 @default.
• W3168889671 cites W2792485323 @default.
• W3168889671 cites W2933160061 @default.
• W3168889671 cites W2995902735 @default.
• W3168889671 cites W3001897055 @default.
• W3168889671 cites W3003217347 @default.
• W3168889671 cites W3004280078 @default.
• W3168889671 cites W3007643904 @default.
• W3168889671 cites W3009335299 @default.
• W3168889671 cites W3009906937 @default.
• W3168889671 cites W3009912996 @default.
• W3168889671 cites W3010441732 @default.
• W3168889671 cites W3011483298 @default.
• W3168889671 cites W3013093478 @default.
• W3168889671 cites W3013800395 @default.
• W3168889671 cites W3013855790 @default.
• W3168889671 cites W3014067025 @default.
• W3168889671 cites W3015134137 @default.
• W3168889671 cites W3015186638 @default.
• W3168889671 cites W3015190630 @default.
• W3168889671 cites W3016535750 @default.
• W3168889671 cites W3017258575 @default.
• W3168889671 cites W3017302293 @default.
• W3168889671 cites W3017309779 @default.
• W3168889671 cites W3017990560 @default.
• W3168889671 cites W3020720269 @default.
• W3168889671 cites W3021655800 @default.
• W3168889671 cites W3021895683 @default.
• W3168889671 cites W3022000877 @default.
• W3168889671 cites W3022735223 @default.
• W3168889671 cites W3023070428 @default.
• W3168889671 cites W3024126428 @default.
• W3168889671 cites W3024602798 @default.
• W3168889671 cites W3025987322 @default.
• W3168889671 cites W3029682964 @default.
• W3168889671 cites W3031272153 @default.
• W3168889671 cites W3031532427 @default.
• W3168889671 cites W3032255042 @default.
• W3168889671 cites W3034828949 @default.
• W3168889671 cites W3036386821 @default.
• W3168889671 cites W3036529319 @default.
• W3168889671 cites W3036931136 @default.
• W3168889671 cites W3039901154 @default.
• W3168889671 cites W3040035440 @default.
• W3168889671 cites W3042332408 @default.
• W3168889671 cites W3042948364 @default.
• W3168889671 cites W3044050454 @default.
• W3168889671 cites W3044321933 @default.
• W3168889671 cites W3049142173 @default.
• W3168889671 cites W3058836816 @default.
• W3168889671 cites W3083130172 @default.
• W3168889671 cites W3084653951 @default.
• W3168889671 cites W3085153423 @default.
• W3168889671 cites W3085586916 @default.
• W3168889671 cites W3085803082 @default.
• W3168889671 cites W3087347658 @default.
• W3168889671 cites W3088579397 @default.
• W3168889671 cites W3090172996 @default.
• W3168889671 cites W3092192687 @default.
• W3168889671 cites W3093061534 @default.
• W3168889671 cites W3093867667 @default.
• W3168889671 cites W3094419073 @default.
• W3168889671 cites W3094617920 @default.
• W3168889671 cites W3096967708 @default.
• W3168889671 cites W3101992496 @default.
• W3168889671 cites W3104432614 @default.
• W3168889671 cites W3104727101 @default.
• W3168889671 cites W3107235131 @default.
• W3168889671 cites W3107327505 @default.

• next