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GPCR Modeling
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Irina D.Pogozheva
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To obtain atomic resolution structures of the transmembrane 7 alpha-bundle of opioid and other G protein-coupled receptors (GPCRS), we have developed a theoretical approach, based on the analysis of correlations in multisequence alignments of 410 GPCRs to pack the 7 alpha-helices using the distance geometry algorithm with an evolving system of interhelical H-bonds, formed by polar side chains in various proteins within the family and collectively applied as distance constraints [Pogozheva et al., 1997].This approach has been used to calculate models of the transmembrane 7 alpha-bundles of 30 different GPCRs and receptor-like proteins. Our model of rhodopsin appeared to be one of the best approximations to the recently resolved crystal structure of bovine rhodopsin (with r.m.s.d 2.88 A; for 186 C-alpha atoms in the transmembrane domain). The crystal structure of rhodopsin is currently used for homology modeling of 7 alpha-bundles of GPCRs from the rhodopin-like subfamily (opioid, PAR, adrenergic, LSH, melanocortin receptors). This homology modeling is supplemented by distance geometry calculations for loop modeling, for structure refinement procedure and for modeling the active receptor conformation, using published distance constraints between labels, introduced in helices 3 and 6.
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An original approach for threading nonhomologous sequences through a structural template that uses new atomic energy functions [Lomize et al., 2002] is under development. This approach is designed for the modeling of GPCRs from the non-rhodopsin families (e.g. secretin, glutamate-receptor and yeast pheromone receptor (STE) families) whose lack of sequence homology to rhodopsin make homology modeling impossible. The approach has much more general applicability, however, which will also be exploited.
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Collaborators Involved
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John R. Traynor
, Ph.D. Sr. Associate Research Scientist, Department of Pharmacology UofM
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Carrie Haskell-Luevano
, Ph.D. Associate Professor Department of Medicinal Chemistry University of Florida
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Related Publications
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Lomize AL, Pogozheva ID, Mosberg HI
Structural organization of G-protein-coupled receptors.
J. Comput. Aided Mol. Des., 13: 325-353 (1999)
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Pogozheva ID, Lomize AL, Mosberg HI
Opioid receptor three-dimensional structures from distance geometry calculations with hydrogen bonding constraints.
Biophys. J., 75: 612-634 (1998)
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Pogozheva ID, Lomize AL, Mosberg HI
The transmembrane 7-alpha-bundle of rhodopsin: distance geometry calculations with hydrogen bonding constraints.
Biophys. J., 72: 1963-1985 (1997)
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Mosberg HI, Fowler CB
Development and validation of opioid ligand-receptor interaction models: The structural basis of mu vs. delta selectivity
J. Peptide Res., 60: 329-332 (2002)
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Fowler CB, Pogozheva ID, LeVine H 3rd, Mosberg HI.
Refinement of a homology model of the mu-opioid receptor using distance constraints from intrinsic and engineered zinc-binding sites.
Biochemistry., 43: 8700-8710 (2004)
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Fowler CB,. Pogozheva ID, Akil H, LeVine III H, Mosberg HI
Determination of the relative positions between TMH V and VI of the mu-opioid receptor using site-directed mutagenesis
Peptides for the New Millennium, Proceedings of the 16th American Peptide Symposium: 374-375 (2000)
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Chai B-X, Pogozheva ID, Lai Y-M, Li J-Y, Neubig RR, Mosberg HI, Gantz I
Receptor-antagonist interactions in the complexes of agouti protein and agouti-related protein with human melanocortin 1 and 4 receptors.
Biochemistry, 44: 3418-3431 (2005)
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Pogozheva ID, Chai B-X, Lomize AL, Fong TM, Weinberg DH, Nargund RH, Mulholland MW, Gantz I, Mosberg HI
Interactions of human melanocortin receptor-4 with small-molecule agonists.
Biochemistry, 44: 11329-11341 (2005)
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Proneth B, Xiang Z, Pogozheva ID, Litherland SA, Gorbatyuk OS, Shaw AM, Millard WJ, Mosberg HI, Haskell-Luevano C
Molecular mechanism of the constitutive activation of the L250Q human melanocortin-4 receptor polymorphism
Chem. Biol. Drug. Des., 67: 215-229 (2006)
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Poulsen A, Bjornholm B, Gundertofte K, Pogozheva ID, Liljefors T
Pharmacophore and receptor models for neurokinin receptors.
J. Comput. Aided. Mol. Des., 17: 765-783 (2003)
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Munshi UM, Pogozheva ID, Menon KM
Highly conserved serine in the third transmembrane helix of the luteinizing hormone/human chorionic gonadotropin receptor regulates receptor activation.
Biochemistry., 42: 3708-3715 (2003)
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External Funding
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DA 03910, H. I. Mosberg, PI
NIH/NIDA
Conformation-Selectivity Relations of Opioid Peptides
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