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Homology modeling of GPCRs, important drug targets
Irina D.Pogozheva , Andrei L.Lomize
A combination of bioinformatics, molecular modeling and experimental techniques is used to obtain structural models of different G protein-coupled receptors, including opioid, melanocortin, PAR, adrenergic, glycoprotein and gonadotropin-releasing hormone receptors. These protein models are invaluable for examining ligand-protein interactions, mechanisms of signaling and transport, to analyze protein polymorphisms, to design site-directed mutagenesis studies, and to develop receptor-specific ligands with desired properties.

Models of active and inactive conformations of mu, delta, kappa and orphanin receptors are being used for structure-based design of opioid ligands with specific binding and activation properties. An example is the design of mixed mu-agonist and delta-antagonist peptides, described elsewhere on this site. Modeling of mutant melanocortin receptors (Figure 1) allowed us to reveal the mechanism of action of ligands that compensate for functional deficiency of MC4R mutants identified in obese humans (in collaboration with C.Haskell-Luevano, University of Florida; S.Farooqi, Cambridge Institute for Medical Research, UK).

Figure 1: MC4 receptor model with docked natural peptide ligand, α-MSH (purple stick). Positions of obesity-associated human polymorphisms are shown by colored balls.

Modeling of complexes of human MC4R mutants with receptor-specific antagonists (with M. Bouvier, Institut de Recherche en Immunologie et en Cancérologie, Université de Montréal, Canada) helped to understand structural requirements that provide rescue activity of pharmacological chaperones toward particular obesity-related MC4R mutants. Pharmacological chaperones are small molecules with antagonist activity that are able to enter cells, bind to misfolded GPCR mutants and stabilize receptor structures that can escape retention by the cellular quality control system and traffic to the plasma membrane, the site of their normal functioning. Pharmacological chaperones thus may have potential therapeutic value in curing diseases related to misfolding and misrouting of mutant GPCRs.

Figure 2: Pharmacological chaperone (purple), able to rescue function of 8 obesity-related mutants, docked in the MC4R model.

Related Publications

Tan K, Pogozheva ID, Yeo GS, Hadaschik D, Keogh JM, Haskell-Leuvano C, O Rahilly S, Mosberg HI, Farooqi IS.
Functional characterization and structural modeling of obesity associated mutations in the melanocortin 4 receptor.
Endocrinology, 150(1): 114-125 (2009)

Haskell-Luevano C, Xiang Z, Wilczynski AM, Haskell KR, Andreasen AM, Litherland SA, Millard WJ, Pogozheva ID, Mosberg HI, Sorenson NB.
Discovery of a ligand that compensates for decreased endogenous agonist potency of melanocortin-4 receptor polymorphisms identified in obese humans.
Adv Exp Med Biol, 611: 509-510 (2009)

Purington LC, Pogozheva ID, Traynor JR, Mosberg HI.
Pentapeptides displaying mu opioid receptor agonist and delta opioid receptor partial agonist/antagonist properties.
J Med Chem, 52(23): 7724-7731 (2009)

Proneth B, Pogozheva ID, Portillo FP, Mosberg HI, Haskell-Luevano C.
Melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 modified at the para position of the benzyl side chain (DPhe): importance for mouse melanocortin-3 receptor agonist versus antagonist activity.
J Med Chem, 51(18): 5585-5593 (2008)

Xiang Z, Pogozheva ID, Sorenson NB, Wilczynski AM, Holder JR, Litherland SA, Millard WJ, Mosberg HI, Haskell-Luevano C.
Peptide and small molecules rescue the functional activity and agonist potency of dysfunctional human melanocortin-4 receptor polymorphisms
Biochemistry, 46(28): 8273-8287 (2007)

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)

Przydzial MJ, Pogozheva ID, Bosse KE, Andrews SM, Tod A, Tharp TA, Traynor JR, Mosberg HI
Roles of residues 3 and 4 in cyclic tetrapeptide ligand recognition by the kappa- opioid receptor
J. Pept. Res., 65: 333-342 (2005)

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)

Przydzial MJ, Pogozheva ID, Ho JC, Tharp TA, Drankhan KE, Sawyer E, Traynor JR, Mosberg HI
Design of high affinity cyclic pentapeptide ligands for kappa-opioid receptors.
J. Pept. Res., 66: 255-262 (2005)

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)

Pogozheva ID, Przydzial MJ, Mosberg HI
Homology modeling of opioid receptor-ligand complexes using experimental constraints.
AAPS J., 7: E434-E448 (2005)

Fowler CB, Pogozheva ID, Lomize AL, LeVine H, Mosberg HI
Complex of active mu-opioid receptor with cyclic peptide agonist modeled from experimental constraints.
Biochemistry, 43: 15796-15810 (2004)

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)

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)

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)

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)

Lomize AL, Pogozheva ID, Mosberg HI
Prediction of protein structure: The problem of fold multiplicity.
Proteins, 37: 199-203 (1999)

Lomize AL, Pogozheva ID, Mosberg HI
Structural organization of G-protein-coupled receptors.
J. Comput. Aided Mol. Des., 13: 325-353 (1999)

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)

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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Design and synthesis of biologically active opioid peptides and peptidomimetics
Investigations of MOR and DOR trafficking and crosstalk
Development of mixed efficacy opioid ligands
Peptides and proteins in membranes
Homology modeling of GPCRs, important drug targets
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