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• W3137205495 abstract "Biological membranes define the boundaries of cells and compartmentalize the chemical and physical processes required for life. Many biological processes are carried out by proteins embedded in or associated with such membranes. Determination of membrane protein (MP) structures at atomic or near-atomic resolution plays a vital role in elucidating their structural and functional impact in biology. This endeavor has determined 1198 unique MP structures as of early 2021. The value of these structures is expanded greatly by deposition of their three-dimensional (3D) coordinates into the Protein Data Bank (PDB) after the first atomic MP structure was elucidated in 1985. Since then, free access to MP structures facilitates broader and deeper understanding of MPs, which provides crucial new insights into their biological functions. Here we highlight the structural and functional biology of representative MPs and landmarks in the evolution of new technologies, with insights into key developments influenced by the PDB in magnifying their impact. Biological membranes define the boundaries of cells and compartmentalize the chemical and physical processes required for life. Many biological processes are carried out by proteins embedded in or associated with such membranes. Determination of membrane protein (MP) structures at atomic or near-atomic resolution plays a vital role in elucidating their structural and functional impact in biology. This endeavor has determined 1198 unique MP structures as of early 2021. The value of these structures is expanded greatly by deposition of their three-dimensional (3D) coordinates into the Protein Data Bank (PDB) after the first atomic MP structure was elucidated in 1985. Since then, free access to MP structures facilitates broader and deeper understanding of MPs, which provides crucial new insights into their biological functions. Here we highlight the structural and functional biology of representative MPs and landmarks in the evolution of new technologies, with insights into key developments influenced by the PDB in magnifying their impact. As membranes were critical to the separation of chemistries essential to the origin of life, membrane proteins (MPs) are key players in some of the most important physiological processes in living organisms. Characterizing MPs structurally and functionally is still extremely challenging due to their frequent low abundance, and difficulties in purifying functional MPs intact from their native membrane, though it is going through an exciting revolution now due to several key factors. It took several decades to obtain the structural information that now allows pursuit of understanding MP function in health and disease, to manipulate them as drug targets, and to engineer them into new powerful tools to fuel discovery. We highlight some of the landmarks in this endeavor that drove or depended on the discovery of new technologies required specifically for structural studies of membrane, versus soluble proteins. Previously, hand-written letters delivered by post requested coordinate sets that were not always readily given. The vision of Hamilton, Myer, Koetzle, and the joint venture between the Cambridge Crystallographic Data Center in the United Kingdom and the Brookhaven National Laboratories at Stony Brook University led to the Protein Data Bank (PDB). Then for the first time, one could begin to ask questions with all the relevant structures at hand. In celebrating 50 years of the PDB, we focus on some of the ingeniously crafted inventions and discoveries that led the way for entire classes of MPs, and those new approaches that now promise structures of large and complex machines from their native cellular environments, in action. In the following Historical perspective, we provide a brief historical perspective of some MP insights (other than the crucial G-protein-coupled receptors (GPCRs) that are the subject of a dedicated review in this volume) and consider the value of the PDB in disseminating this information. Seemingly insurmountable difficulties were often overcome with invention of new technologies to reveal important structural features of classes of MPs that make the fabric of today's approaches. In How do membrane proteins accomplish key physiological functions?, we describe how the structures of several of the major MP classes were uncovered, which often required technological developments that are now woven into the fabric of structural biology. First, how are the α-helical, tail-anchored, and all β-sheet MP broad categories correctly targeted to and inserted into membranes and allowed to fold correctly? We progress to landmark discoveries involving the roles of MPs in physiology and some of the critical barriers that had to be overcome to realize these achievements. How do water channels conduct water at diffusion limited rates without allowing leakage of protons (H+) or hydronium ions (H3O+) or any other ions? How do potassium channels conduct K+ ions, but not the Na+ ion of similar charge and smaller ionic radius? How are epithelial cells held together side by side to make a selectively permeable sealed layer of cells? The question of how substrates are transported across membranes using energy then follows. How does one superfamily of “primary” transporters, the “ABC transporters” that directly harness ATP hydrolysis on their cytoplasmic side, move materials across membranes? How does another superfamily of “secondary” transporters, the Major Facilitator Superfamily (MFS), use ion or proton electrochemical gradients to drive nutrient import, export, or efflux of xenobiotics? We progress to consider a specialized class of essential viral proteins that form channels that are essential for viral virulence. In Membrane protein structures instruct drug design and protein engineering, we focus on a few examples of therapeutics and opportunities for engineering of MPs. Critical to any therapeutic drugs are the membrane-attached cytochrome P450s that are discussed in the light of their key roles in sterol metabolism, but as metabolizers of therapeutic drugs, and therefore as drug targets themselves. Structures help elucidate mechanisms of action of therapeutics to modulate MP activities. The Cystic Fibrosis Transmembrane-Conductance Regulator (CFTR) is used as an example of the impact structural studies can have on the understanding and treatment of rare diseases. Another example addresses glucose import as an anticancer target opportunity. A key example in neurology is the class of ligand-gated ion channels, represented by GABAA receptors (GABAAR) and their ligands. Then the Leucine Transporter (LeuT), representing several classes of transporters with a common core of ten trans-membrane α-helices (TMs), is used to illustrate how major antidepressants work. Finally, some exciting developments in MP engineering focus on channelrhodopsins where light can trigger cellular responses and engineered dopamine sensors. We hope that this necessarily limited perspective on the impact of selected MP structure classes may encourage opportunities in a broader context. We hope to communicate the value of MPs as guardians of the health of cells and how their structures, through the PDB, contribute important insights into many crucial aspects of physiology. With soluble proteins beginning with myoglobin in 1961, followed by lysozyme, hemoglobin, and digestive proteases, these were available only from large animals or from bacteria. Long before overexpression systems became available, the number of soluble macromolecular structures followed an exponential growth. This pattern was noted by Dickerson in a letter written to the PDB in 1978 (1Dickerson R.E. PDB.Newsletter. 2002; 13: 3Google Scholar). The first integral MP structure was not determined until 25 years later in 1985. The number of MP structures determined and deposited in the PDB since that time also increased exponentially, but with a smaller exponent reflecting the considerable challenges that pertain to MP structural biology. The amount of time for the number of unique MP structures to double was about 3 years compared with 2.4 years for soluble macromolecules (2White S.H. Biophysical dissection of membrane proteins.Nature. 2009; 459: 344-346Crossref PubMed Scopus (205) Google Scholar). This doubling time for MPs slowed to ∼5 years recently (Fig. 1). Most obvious challenges are functional expression in a limited lipid membrane environment versus expression in a soluble volume, followed by the requirement for detergents, amphiphiles, and lipids during extraction and purification of functional proteins from the membrane. There were critical breakthroughs necessary for many new classes of MPs over the last three decades. As a reflection, on January 15th, 2021, there were a total of 4569 coordinate files for MPs in the PDB, barely 2.6% of the total for all proteins, and of these 1203 represent unique structures. This is brilliantly tracked and annotated by Stephen H. White’s invaluable mpstruct database of MPs of known structure (Fig. 1) (2White S.H. Biophysical dissection of membrane proteins.Nature. 2009; 459: 344-346Crossref PubMed Scopus (205) Google Scholar) (https://blanco.biomol.uci.edu/mpstruc/), and by statistical and thermodynamic analyses from Thomas Newport, Mark Sansom, and Phillip Stansfield in their MemProtMD database (3Newport T.D. Sansom M.S.P. Stansfeld P.J. The MemProtMD database: A resource for membrane-embedded protein structures and their lipid interactions.Nucleic Acids Res. 2019; 47: D390-D397Crossref PubMed Scopus (41) Google Scholar). One of our aims here is to celebrate some of these developments in association with the breakthroughs by those that made them possible. Like those in the 1960s who worked on the soluble proteins available in quantity from the tissues of large animals or bacteria, work on the first MP structures also focused on rich natural sources. The purple membrane of archaebacteria was first described in 1971 by Oesterhelt and Stoeckenius, who showed that it contained a light-driven proton pump. This validated the Mitchell hypothesis, the revolutionary concept that biological energy could be stored as a proton gradient across a membrane (4Oesterhelt D. Stoeckenius W. Rhodopsin-like protein from the purple membrane of Halobacterium halobium.Nat. New Biol. 1971; 233: 149-152Crossref PubMed Google Scholar, 5Racker E. Stoeckenius W. Reconstitution of purple membrane vesicles catalyzing light-driven proton uptake and adenosine triphosphate formation.J. Biol. Chem. 1974; 249: 662-663Abstract Full Text PDF PubMed Google Scholar). By freeze-fracture electron microscopy, they showed that “bacteriorhodopsin” formed an in-plane trigonal two-dimensional (2D) lattice. This was pursued structurally by Henderson and Unwin using electron diffraction of the arrays formed in the membrane (6Henderson R. Unwin P.N. Three-dimensional model of purple membrane obtained by electron microscopy.Nature. 1975; 257: 28-32Crossref PubMed Scopus (0) Google Scholar), by Michel working with Oesterhelt, who attempted to crystallize the protein using detergents (7Michel H. Oesterhelt D. Electrochemical proton gradient across the cell membrane of Halobacterium halobium: Comparison of the light-induced increase with the increase of intracellular adenosine triphosphate under steady-state illumination.Biochemistry. 1980; 19: 4615-4619Crossref PubMed Google Scholar, 8Michel H. Oesterhelt D. Three-dimensional crystals of membrane proteins: Bacteriorhodopsin.Proc. Natl. Acad. Sci. U. S. A. 1980; 77: 1283-1285Crossref PubMed Google Scholar, 9Michel H. Oesterhelt D. Henderson R. Orthorhombic two-dimensional crystal form of purple membrane.Proc. Natl. Acad. Sci. U. S. A. 1980; 77: 338-342Crossref PubMed Google Scholar, 10Michel H. Characterization and crystal packing of three-dimensional bacteriorhodopsin crystals.EMBO J. 1982; 1: 1267-1271Crossref PubMed Google Scholar), and by Blaurock using X-ray scattering to demonstrate that α-helices were oriented perpendicular to the membrane plane (11Blaurock A.E. Stoeckenius W. Structure of the purple membrane.Nat. New Biol. 1971; 233: 152-155Crossref PubMed Google Scholar, 12Blaurock A.E. Bacteriorhodospin: A trans-membrane pump containing alpha-helix.J. Mol. Biol. 1975; 93: 139-158Crossref PubMed Scopus (0) Google Scholar). Henderson and Unwin produced the first electron diffraction patterns from the trigonal latticed membranes, purified from the natural source, by sustaining its single bilayer in a glucose solution to prevent dehydration in the electron microscope (6Henderson R. Unwin P.N. Three-dimensional model of purple membrane obtained by electron microscopy.Nature. 1975; 257: 28-32Crossref PubMed Scopus (0) Google Scholar). In a towering landmark, in 1975, they phased the patterns based on the images and reconstructed a 7 Å resolution 3D structure that beautifully demonstrated that the protein is comprised of seven TMs (6Henderson R. Unwin P.N. Three-dimensional model of purple membrane obtained by electron microscopy.Nature. 1975; 257: 28-32Crossref PubMed Scopus (0) Google Scholar). This first discovery using electron microscopy/diffraction was at the heart of the concepts later recognized by the Nobel prize in chemistry to Henderson, Frank, and Dubochet in 2017. Soon after, in 1977 to 1979, the amino acid sequence of bacteriorhodopsin was determined by the groups of Khorana (13Khorana H.G. Gerber G.E. Herlihy W.C. Gray C.P. Anderegg R.J. Nihei K. Biemann K. Amino acid sequence of bacteriorhodopsin.Proc. Natl. Acad. Sci. U. S. A. 1979; 76: 5046-5050Crossref PubMed Scopus (360) Google Scholar) and Ovchinikov (14Ovchinnikov Y.A. Abdulaev N.G. Feigina M.Y. Kiselev A.V. Lobanov N.A. Recent findings in the structure-functional characteristics of bacteriorhodopsin.FEBS Lett. 1977; 84: 1-4Crossref PubMed Scopus (0) Google Scholar, 15Ovchinnikov Y.A. Abdulaev N.G. Feigina M.Y. Kiselev A.V. Lobanov N.A. The structural basis of the functioning of bacteriorhodopsin: An overview.FEBS Lett. 1979; 100: 219-224Crossref PubMed Scopus (324) Google Scholar) using chemical sequencing methods. Agard and Stroud developed computational ways to extend resolution perpendicular to the membrane plane in attempts to reveal the interhelix linker regions to map sequence into the structure from electron diffraction data (16Agard D.A. Stroud R.M. Linking regions between helices in bacteriorhodopsin revealed.Biophys. J. 1982; 37: 589-602Crossref PubMed Google Scholar). With Glaeser, who pioneered low-temperature electron microscopy (17Hayward S.B. Grano D.A. Glaeser R.M. Fisher K.A. Molecular orientation of bacteriorhodopsin within the purple membrane of Halobacterium halobium.Proc. Natl. Acad. Sci. U. S. A. 1978; 75: 4320-4324Crossref PubMed Google Scholar, 18Jap B.K. Maestre M.F. Hayward S.B. Glaeser R.M. Peptide-chain secondary structure of bacteriorhodopsin.Biophys. J. 1983; 43: 81-89Abstract Full Text PDF PubMed Google Scholar), Hayward and Stroud developed a way of aligning microcrystalline regions to extend resolution of the reconstructions to 3.8 Å in-plane resolution (19Hayward S.B. Stroud R.M. Projected structure of purple membrane determined to 3.7 A resolution by low temperature electron microscopy.J. Mol. Biol. 1981; 151: 491-517Crossref PubMed Scopus (63) Google Scholar). As a reflection of the extreme challenges for membrane versus soluble proteins, the bacteriorhodopsin structure reached atomic resolution by electron diffraction 20 years after the 1975 breakthrough in 1996 (20Grigorieff N. Beckmann E. Zemlin F. Lipid location in deoxycholate-treated purple membrane at 2.6 A.J. Mol. Biol. 1995; 254: 404-415Crossref PubMed Google Scholar, 21Grigorieff N. Ceska T.A. Downing K.H. Baldwin J.M. Henderson R. Electron-crystallographic refinement of the structure of bacteriorhodopsin.J. Mol. Biol. 1996; 259: 393-421Crossref PubMed Scopus (841) Google Scholar) and by X-ray diffraction in 1997 (22Pebay-Peyroula E. Rummel G. Rosenbusch J.P. Landau E.M. X-ray structure of bacteriorhodopsin at 2.5 angstroms from microcrystals grown in lipidic cubic phases.Science. 1997; 277: 1676-1681Crossref PubMed Scopus (798) Google Scholar) (Fig. 1). The cytochrome oxidase from bovine tissues (23Gennis R. Ferguson-Miller S. Structure of cytochrome c oxidase, energy generator of aerobic life.Science. 1995; 269: 1063-1064Crossref PubMed Scopus (51) Google Scholar, 24Tsukihara T. Aoyama H. Yamashita E. Tomizaki T. Yamaguchi H. Shinzawa-Itoh K. Nakashima R. Yaono R. Yoshikawa S. Structures of metal sites of oxidized bovine heart cytochrome c oxidase at 2.8 A.Science. 1995; 269: 1069-1074Crossref PubMed Google Scholar) and the acetylcholine receptor from electric rays and eels (25Schmidt J. Raftery M.A. Purification of acetylcholine receptors from Torpedo californica electroplax by affinity chromatography.Biochemistry. 1973; 12: 852-856Crossref PubMed Google Scholar, 26Raftery M.A. Vandlen R. Michaelson D. Bode J. Moody T. Chao Y. Reed K. Deutsch J. Duguid J. The biochemistry of an acetylcholine receptor.J. Supramol. Struct. 1974; 2: 582-592Crossref PubMed Google Scholar, 27Devillers-Thiery A. Changeux J.P. Paroutaud P. Strosberg A.D. The amino-terminal sequence of the 40,000 molecular weight subunit of the acetylcholine receptor protein from Torpedo marmorata.FEBS Lett. 1979; 104: 99-105Crossref PubMed Scopus (0) Google Scholar, 28Raftery M.A. Hunkapiller M.W. Strader C.D. Hood L.E. Acetylcholine receptor: Complex of homologous subunits.Science. 1980; 208: 1454-1456Crossref PubMed Google Scholar, 29Devillers-Thiery A. Giraudat J. Bentaboulet M. Changeux J.P. Complete mRNA coding sequence of the acetylcholine binding alpha-subunit of Torpedo marmorata acetylcholine receptor: A model for the transmembrane organization of the polypeptide chain.Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 2067-2071Crossref PubMed Google Scholar), respectively, key to oxidative phosphorylation in mitochondria (see Early breakthroughs in High Resolution Structures of Bioenergetic Membrane Complexes and Lipid Interactions) and function of the neuromuscular junction, also provided highly important sources of MP complexes. Beginning in 1971, the first 3D surface shapes of the acetylcholine receptor ∼300 kDa complex of five homologous subunits in a quasi-fivefold pentameric complex αβαγδ were revealed using low-dose negative stain EM and small-angle X-ray scattering from stacked membranes by Stroud and Unwin (30Ross M.J. Klymkowsky M.W. Agard D.A. Stroud R.M. Structural studies of a membrane-bound acetylcholine receptor from Torpedo californica.J. Mol. Biol. 1977; 116: 635-659Crossref PubMed Scopus (0) Google Scholar, 31Kistler J. Stroud R.M. Crystalline arrays of membrane-bound acetylcholine receptor.Proc. Natl. Acad. Sci. U. S. A. 1981; 78: 3678-3682Crossref PubMed Google Scholar, 32Kistler J. Stroud R.M. Klymkowsky M.W. Lalancette R.A. Fairclough R.H. Structure and function of an acetylcholine receptor.Biophys. J. 1982; 37: 371-383Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 33Brisson A. Unwin P.N. Tubular crystals of acetylcholine receptor.J. Cell Biol. 1984; 99: 1202-1211Crossref PubMed Google Scholar, 34Brisson A. Unwin P.N. Quaternary structure of the acetylcholine receptor.Nature. 1985; 315: 474-477Crossref PubMed Google Scholar, 35Mitra A.K. McCarthy M.P. Stroud R.M. Three-dimensional structure of the nicotinic acetylcholine receptor and location of the major associated 43-kD cytoskeletal protein, determined at 22 A by low dose electron microscopy and x-ray diffraction to 12.5 A.J. Cell Biol. 1989; 109: 755-774Crossref PubMed Google Scholar). The primary sequence, determined initially by Michael Raftery using amino acid sequencing for 50 amino acids of each of the four homologous subunits (28Raftery M.A. Hunkapiller M.W. Strader C.D. Hood L.E. Acetylcholine receptor: Complex of homologous subunits.Science. 1980; 208: 1454-1456Crossref PubMed Google Scholar, 36Hunkapiller M.W. Strader C.D. Hood L. Raftery M.A. Amino terminal amino acid sequence of the major polypeptide subunit of Torpedo californica acetylcholine receptor.Biochem. Biophys. Res. Commun. 1979; 91: 164-169Crossref PubMed Scopus (19) Google Scholar), and in parallel by Jean-Pierre Changeux for the α-chain N-terminal sequence (27Devillers-Thiery A. Changeux J.P. Paroutaud P. Strosberg A.D. The amino-terminal sequence of the 40,000 molecular weight subunit of the acetylcholine receptor protein from Torpedo marmorata.FEBS Lett. 1979; 104: 99-105Crossref PubMed Scopus (0) Google Scholar, 29Devillers-Thiery A. Giraudat J. Bentaboulet M. Changeux J.P. Complete mRNA coding sequence of the acetylcholine binding alpha-subunit of Torpedo marmorata acetylcholine receptor: A model for the transmembrane organization of the polypeptide chain.Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 2067-2071Crossref PubMed Google Scholar), led to the cloning and sequencing of the genes (37Noda M. Takahashi H. Tanabe T. Toyosato M. Kikyotani S. Furutani Y. Hirose T. Takashima H. Inayama S. Miyata T. Numa S. Structural homology of Torpedo californica acetylcholine receptor subunits.Nature. 1983; 302: 528-532Crossref PubMed Scopus (524) Google Scholar). It became clear that like bacteriorhodopsin, it too contained TMs. The right-handed α-helix first delineated by Pauling (38Pauling L. Corey R.B. Branson H.R. The structure of proteins; two hydrogen-bonded helical configurations of the polypeptide chain.Proc. Natl. Acad. Sci. U. S. A. 1951; 37: 205-211Crossref PubMed Google Scholar) provided the necessary shielding of all polar groups, namely the carbonyls and amides of the polypeptide backbone. Hence, a sequence of ∼19 hydrophobic amino acids became a recognizable signal for TMs, while strongly amphipathic helices signal membrane surface-seeking helices (39Finer-Moore J. Stroud R.M. Amphipathic analysis and possible formation of the ion channel in an acetylcholine receptor.Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 155-159Crossref PubMed Google Scholar). Remarkable insights followed from the few MP structures already determined, including the finding that their hydrophobic helices formed well-ordered 3D structures in lipid bilayer membranes and their retention even after gentle extraction in amphiphiles and detergents. Yet it took 45 years to obtain the first atomic structures for the acetylcholine receptor. This required screening of many specific genetic constructs of several members of this receptor family (40Unwin N. Nicotinic acetylcholine receptor and the structural basis of neuromuscular transmission: Insights from Torpedo postsynaptic membranes.Q. Rev. Biophys. 2013; 46: 283-322Crossref PubMed Google Scholar, 41Morales-Perez C.L. Noviello C.M. Hibbs R.E. X-ray structure of the human alpha4beta2 nicotinic receptor.Nature. 2016; 538: 411-415Crossref PubMed Scopus (238) Google Scholar). The first atomic resolution structure of any integral MP came from the group of Michel in 1985 (42Deisenhofer J. Epp O. Miki K. Huber R. Michel H. X-ray structure analysis of a membrane protein complex. Electron density map at 3 A resolution and a model of the chromophores of the photosynthetic reaction center from Rhodopseudomonas viridis.J. Mol. Biol. 1984; 180: 385-398Crossref PubMed Scopus (1498) Google Scholar). After many years trying to crystallize bacteriorhodopsin, Michel and Oesterhelt had appreciated the value of colored proteins such as bacteriorhodopsin. Visible bands on columns aided purification, and more importantly, where the color of unique spectral features reflected the integrity of the MP (43Milder S.J. Thorgeirsson T.E. Miercke L.J. Stroud R.M. Kliger D.S. Effects of detergent environments on the photocycle of purified monomeric bacteriorhodopsin.Biochemistry. 1991; 30: 1751-1761Crossref PubMed Google Scholar) and signaled for monitoring structural preservation in harsh solubilizing detergents. Using photobacteria as a rich source of photosynthetic proteins, Michel and colleagues determined the first MP structure from crystals that diffracted to atomic resolution (3 Å and then at 2.3 Å). The structure of the Rhodopseudomonas viridis photosynthetic reaction center of 145 kDa published in 1984 (42Deisenhofer J. Epp O. Miki K. Huber R. Michel H. X-ray structure analysis of a membrane protein complex. Electron density map at 3 A resolution and a model of the chromophores of the photosynthetic reaction center from Rhodopseudomonas viridis.J. Mol. Biol. 1984; 180: 385-398Crossref PubMed Scopus (1498) Google Scholar) remains an amazing achievement. It showed that the predominantly hydrophobic α-helices are often longer than enough to span the 40 Å bilayer and can be correspondingly tilted at different angles to harbor the many chromophores that harness the light that supports life. This breakthrough discovery was recognized by the Nobel prize in chemistry in 1988 to Michel, Deisenhofer, and Huber (Fig. 1). Ion channels in membranes were in the limelight because they accounted for the currents across membranes that are key to the nervous system, as described by Hodgkin, Huxley, and Katz in 1952 (44Hodgkin A.L. Huxley A.F. Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo.J. Physiol. 1952; 116: 449-472Crossref PubMed Google Scholar, 45Hodgkin A.L. Huxley A.F. Movement of sodium and potassium ions during nervous activity.Cold Spring Harb. Symp. Quant. Biol. 1952; 17: 43-52Crossref PubMed Scopus (0) Google Scholar, 46Hodgkin A.L. Huxley A.F. Katz B. Measurement of current-voltage relations in the membrane of the giant axon of Loligo.J. Physiol. 1952; 116: 424-448Crossref PubMed Google Scholar), and beautifully elaborated since then. The key was that Na+ ions are consistently pumped out of the mammalian cell using energy from ATP hydrolysis, while potassium ions remain inside to balance the electrochemical potential across the plasma membranes according to the Nernst equation. In neurons, however, the need for fast communication relies on rapid conduction of the Na+ ions inward that is signaled by the release of neurotransmitters at neuronal synapses that depolarize the plasma membranes of the target cell. This is then rapidly followed by release of K+ ions though highly selective channels that do not leak the smaller Na+ ions, but restore the transmembrane electrical potential. How is such selectivity accomplished? The alkali metal Na+ and K+ ions differ in ionic radius, yet why don’t K+ channels leak the smaller Na+ ion? The answer came in MacKinnon’s finding that bacterial K+ channels existed and could be extracted for structure determination. In 1998, he reported the first K+ channel structure (KcsA) from the bacterium Streptomyces lividans (47Doyle D.A. Morais Cabral J. Pfuetzner R.A. Kuo A. Gulbis J.M. Cohen S.L. Chait B.T. MacKinnon R. The structure of the potassium channel: Molecular basis of K+ conduction and selectivity.Science. 1998; 280: 69-77Crossref PubMed Scopus (5443) Google Scholar). The structure showed precisely how its selectivity was achieved. The key was in the precise arrangement of a fourfold arrangement of lines of carbonyl oxygens that surround a “selectivity filter” (SF) in the pore entry. They provide the precise counterpart for the normal water hydration shell around the K+ ion, but were too far apart to provide similar energy balance for the Na+ ion. MacKinnon was awarded the Nobel Prize in chemistry for this landmark discovery in 2003 (Fig. 1). The 2003 Nobel prize in chemistry was shared with Agre, recognizing another remarkable discovery, that of water channels (48Preston G.M. Carroll T.P. Guggino W.B. Agre P. Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein.Science. 1992; 256: 385-387Crossref PubMed Google Scholar). In 1985, Benga et al. (49Benga G. Popescu O. Borza V. Pop V.I. Muresan A. Mocsy I. Brain A. Wrigglesworth J.M. Water permeability in human erythrocytes: Identification of membrane proteins involved in water transport.Eur. J. Cell Biol. 1986; 41: 252-262PubMed Google Scholar, 50Benga G. Popescu O. Pop V.I. Holmes R.P. p-(Chloromercuri)benzenesulfonate binding by membrane proteins and the inhibition of water transport in human erythrocytes.Biochemistry. 1986; 25: 1535-1538Crossref PubMed Google Scholar) demonstrated that red blood cells had water channels that were inhibitable by mercurials, implying that a sulfhydryl containing protein was responsible. They showed that this was true across many (now all) species, and Nielsen and Agre (51Nielsen S. Agre P. The aquaporin family of water channels in kidney.Kidney Int. 1995; 48: 1057-1068Abstract Full Text PDF PubMed Google Scholar) showed that water channels presented in all cells but for various physiological purposes. They showed that there were 13 different variants in human tissues and named them Aquaporins (AQPs) (52Agre P. Preston G.M. Smith B.L. Jung J.S. Raina S. Moon C. Guggino W.B. Nielsen S. Aquaporin CHIP: The archetypal molecular water channel.Am. J. Physiol. 1993; 265: F463-F476Crossref PubMed Google Scholar). These were more difficult to recognize than ion channels because there were no electrical properties to measure their activity. Their discovery was made while searching for the well-known rhesus (Rh) factors in red blood cells. They discovered a second major MP in these cells, and then showed that it conducted water, and at a speed up to the diffusion-limited values for a pore of the requisite size (see below). Structures of the aquaporins were determined in 2000 by electron imaging (53Murata K. Mitsuoka K. Hirai T. Walz T. Agre P. Heymann J.B. Engel A. Fujiyoshi Y. Structural determinants of water permeation through aquaporin-1.Nature. 2000; 407: 599-605Crossref PubMed Scopus (1306) Google Scholar) and at atomic resolution by X-ray crystallography (54Fu D.X. Libson A. Miercke L.J.W. Weitzman C." @default.
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• W3137205495 title "Highlighting membrane protein structure and function: A celebration of the Protein Data Bank" @default.
• W3137205495 cites W101880175 @default.
• W3137205495 cites W1139015881 @default.
• W3137205495 cites W137530444 @default.
• W3137205495 cites W1495101953 @default.
• W3137205495 cites W1501694644 @default.
• W3137205495 cites W1502708911 @default.
• W3137205495 cites W1509371781 @default.
• W3137205495 cites W1549007983 @default.
• W3137205495 cites W1550259003 @default.
• W3137205495 cites W1552188451 @default.
• W3137205495 cites W1571164133 @default.
• W3137205495 cites W1590125256 @default.
• W3137205495 cites W1606935319 @default.
• W3137205495 cites W1714769843 @default.
• W3137205495 cites W1770155443 @default.
• W3137205495 cites W1845114139 @default.
• W3137205495 cites W1888485834 @default.
• W3137205495 cites W1890431460 @default.
• W3137205495 cites W1908131908 @default.
• W3137205495 cites W1909250730 @default.
• W3137205495 cites W1912107272 @default.
• W3137205495 cites W1916240481 @default.
• W3137205495 cites W1916260872 @default.
• W3137205495 cites W1932059283 @default.
• W3137205495 cites W1941815855 @default.
• W3137205495 cites W1947481567 @default.
• W3137205495 cites W1947778485 @default.
• W3137205495 cites W1954570499 @default.
• W3137205495 cites W1956486503 @default.
• W3137205495 cites W1963871902 @default.
• W3137205495 cites W1964332144 @default.
• W3137205495 cites W1965285497 @default.
• W3137205495 cites W1965325224 @default.
• W3137205495 cites W1965328381 @default.
• W3137205495 cites W1965330913 @default.
• W3137205495 cites W1965962622 @default.
• W3137205495 cites W1966236299 @default.
• W3137205495 cites W1966438745 @default.
• W3137205495 cites W1967297467 @default.
• W3137205495 cites W1968094907 @default.
• W3137205495 cites W1968140392 @default.
• W3137205495 cites W1968400590 @default.
• W3137205495 cites W1968682237 @default.
• W3137205495 cites W1968898370 @default.
• W3137205495 cites W1969549030 @default.
• W3137205495 cites W1969633341 @default.
• W3137205495 cites W1969697265 @default.
• W3137205495 cites W1972116208 @default.
• W3137205495 cites W1972125463 @default.
• W3137205495 cites W1972772651 @default.
• W3137205495 cites W1972784441 @default.
• W3137205495 cites W1972882396 @default.
• W3137205495 cites W1973064936 @default.
• W3137205495 cites W1973538068 @default.
• W3137205495 cites W1973624196 @default.
• W3137205495 cites W1973796039 @default.
• W3137205495 cites W1974423301 @default.
• W3137205495 cites W1974452612 @default.
• W3137205495 cites W1974572661 @default.
• W3137205495 cites W1975641381 @default.
• W3137205495 cites W1976003675 @default.
• W3137205495 cites W1976116333 @default.
• W3137205495 cites W1976394766 @default.
• W3137205495 cites W1977467280 @default.
• W3137205495 cites W1977568392 @default.
• W3137205495 cites W1977593992 @default.
• W3137205495 cites W1978530172 @default.
• W3137205495 cites W1978680299 @default.
• W3137205495 cites W1978886142 @default.
• W3137205495 cites W1979678390 @default.
• W3137205495 cites W1979838358 @default.
• W3137205495 cites W1980741996 @default.
• W3137205495 cites W1981526758 @default.
• W3137205495 cites W1981760537 @default.
• W3137205495 cites W1982230840 @default.
• W3137205495 cites W1982371070 @default.
• W3137205495 cites W1982970909 @default.
• W3137205495 cites W1983041459 @default.
• W3137205495 cites W1983464528 @default.
• W3137205495 cites W1983636667 @default.
• W3137205495 cites W1984522801 @default.
• W3137205495 cites W1984550703 @default.

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