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• W2008035364 endingPage "2604" @default.
• W2008035364 startingPage "2593" @default.
• W2008035364 abstract "G protein-coupled receptors contain selectively important residues that play central roles in the conformational changes that occur during receptor activation. Asparagine 111 (N111(3.35)) is such a residue within the angiotensin II type 1 (AT(1)) receptor. Substitution of N111(3.35) for glycine leads to a constitutively active receptor, whereas substitution for tryptophan leads to an inactivable receptor. Here, we analyzed the AT(1) receptor and two mutants (N111G and N111W) by molecular dynamics simulations, which revealed a novel molecular switch involving the strictly conserved residue D74(2.50). Indeed, D74(2.50) forms a stable hydrogen bond (H-bond) with the residue in position 111(3.35) in the wild-type and the inactivable receptor. However, in the constitutively active mutant N111G-AT(1) receptor, residue D74 is reoriented to form a new H-bond with another strictly conserved residue, N46(1.50). When expressed in HEK293 cells, the mutant N46G-AT(1) receptor was poorly activable, although it retained a high binding affinity. Interestingly, the mutant N46G/N111G-AT(1) receptor was also inactivable. Molecular dynamics simulations also revealed the presence of a cluster of hydrophobic residues from transmembrane domains 2, 3, and 7 that appears to stabilize the inactive form of the receptor. Whereas this hydrophobic cluster and the H-bond between D74(2.50) and W111(3.35) are more stable in the inactivable N111W-AT(1) receptor, the mutant N111W/F77A-AT(1) receptor, designed to weaken the hydrophobic core, showed significant agonist-induced signaling. These results support the potential for the formation of an H-bond between residues D74(2.50) and N46(1.50) in the activation of the AT(1) receptor." @default.
• W2008035364 created "2016-06-24" @default.
• W2008035364 creator A5003738322 @default.
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• W2008035364 creator A5036986482 @default.
• W2008035364 creator A5068043760 @default.
• W2008035364 creator A5075307650 @default.
• W2008035364 date "2013-01-01" @default.
• W2008035364 modified "2023-10-15" @default.
• W2008035364 title "Critical Hydrogen Bond Formation for Activation of the Angiotensin II Type 1 Receptor" @default.
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• W2008035364 doi "https://doi.org/10.1074/jbc.m112.395939" @default.
• W2008035364 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3554926" @default.
• W2008035364 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23223579" @default.
• W2008035364 hasPublicationYear "2013" @default.
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