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Opioid receptor-ligand complexes
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Irina D.Pogozheva
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Our complementary studies elucidating the bioactive conformations of opioid ligands at delta and mu receptors and the development of accurate structural models for these receptors have allowed us to propose models of the ligand-receptor complexes. To evaluate these models we have designed receptor mutants employing several strategies. Among these are: 1) the design of metal-ion-binding centers, formed by His and Cys residues between adjacent transmembrane helices of μ-opioid receptors to better define the relative orientation between these adjacent helices; 2) the design of metal-ion-binding centers between helices and extracellular loops, to better probe the positioning of the more flexible loops and their involvement in ligand binding; and 3) the design of metal-ion-binding centers between receptor and ligand residues and the design of complementary receptor/ligand mutations to confirm specific ligand-receptor interactions. These ongoing studies allow continuing refinement of our models of ligand-receptor complexes, which serve as the basis for our current structure-based ligand design.
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Low affinity mu-opioid agonist improves binding after Zn+2 -coordination by His297, Cys300 of receptor and His1 of mu-agonist KSK-73
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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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Related Publications
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Mosberg HI
Complementarity of delta opioid ligand pharmacophore and receptor models.
Biopolymers, 51: 426-39 (1999)
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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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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, 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)
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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)
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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)
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Pogozheva ID, Przydzial MJ, Mosberg HI
Homology modeling of opioid receptor-ligand complexes using experimental constraints.
AAPS J., 7: E434-E448 (2005)
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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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