Key Residues Defining the μ‐Opioid Receptor Binding Pocket: A Site‐Directed Mutagenesis Study

Mansour, Alfred; Taylor, Larry P.; Fine, Jeffrey L.; Thompson, Robert C.; Hoversten, Mary T.; Mosberg, Henry I.; Watson, Stanley J.; Akil, Huda

doi:10.1046/j.1471-4159.1997.68010344.x

Cited by 125 publications

(116 citation statements)

References 26 publications

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“…It had previously been hypothesized that a positively charged amino substituent would form a salt bridge with a negatively charged aspartate residue, which is highly conserved within the third transmembrane domain of the opioid receptor (Surratt et al, 1994;Mansour et al, 1997;Lu et al, 2001). The lack of such functionality within the tricyclic skeleton makes it unlikely that these ionic interactions are stabilizing salvinorin A in a manner similar to that of other nitrogenous opioids.…”

Section: B Proposed Binding Interactions With -Opioid Receptorsmentioning

confidence: 99%

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

2011

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Section: B Proposed Binding Interactions With -Opioid Receptorsmentioning

confidence: 99%

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

2011

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“…39 , 40 The residues from the binding pocket, essential for ligand binding, are mostly conserved across the ORs and include Asp(3.32), Tyr(3.33), Lys(5.39), Phe(5.47), Trp(6.48), Ile(6.51), His(6.52), Ile(6.53), Ile(7.39), and Tyr(7.43). [41][42][43][44][45][46][47][48][49][50] Binding determinants for small alkaloids (morphine, codeine) reside in TMs 5 -7. 51 Variable binding pocket residues confer selectivity.…”

Section: Experimental Studies Of Receptor-ligand Interactionsmentioning

confidence: 99%

Homology modeling of opioid receptor-ligand complexes using experimental constraints

Pogozheva

Przydzial

Mosberg

2005

AAPS J

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A BSTRACTOpioid receptors interact with a variety of ligands, including endogenous peptides, opiates, and thousands of synthetic compounds with different structural scaffolds. In the absence of experimental structures of opioid receptors, theoretical modeling remains an important tool for structurefunction analysis. The combination of experimental studies and modeling approaches allows development of realistic models of ligand-receptor complexes helpful for elucidation of the molecular determinants of ligand affi nity and selectivity and for understanding mechanisms of functional agonism or antagonism. In this review we provide a brief critical assessment of the status of such theoretical modeling and describe some common problems and their possible solutions. Currently, there are no reliable theoretical methods to generate the models in a completely automatic fashion. Models of higher accuracy can be produced if homology modeling, based on the rhodopsin X-ray template, is supplemented by experimental structural constraints appropriate for the active or inactive receptor conformations, together with receptor-specifi c and ligand-specifi c interactions. The experimental constraints can be derived from mutagenesis and cross-linking studies, correlative replacements of ligand and receptor groups, and incorporation of metal binding sites between residues of receptors or receptors and ligands. This review focuses on the analysis of similarity and differences of the refi ned homology models of m , d , and k -opioid receptors in active and inactive states, emphasizing the molecular details of interaction of the receptors with some representative peptide and nonpeptide ligands, underlying the multiple modes of binding of small opiates, and the differences in binding modes of agonists and antagonists, and of peptides and alkaloids.K EYWORDS: ligand docking , modeling , opioid receptors , opioid ligands , pharmacophore model INTRODUCTIONClinical interest in opioid receptors (ORs) is related to the development of strong analgesics without potential for abuse or adverse side effects. This task, however, cannot be accomplished without understanding the differences in the OR subtypes as well as the modes of interactions of drugs/ ligands with these receptors.Research on ORs was signifi cantly advanced by the cloning of d -opioid (DOR), m -opioid (MOR), and k -opioid (KOR) receptors in the early 1990s. 1 , 2 Sequence comparison confi rmed that ORs belong to the rhodopsin-like family of G-protein-coupled receptors (GPCRs). 1 ORs are composed of a core domain of 7 transmembrane (TM) a -helices and an adjacent, peripheral helix 8 (IL4), are connected by 3 extracellular (EL1, EL2, EL3) and 3 intracellular (IL1, IL2, IL3) loops, and contain glycosylated N-terminal and palmitoylated C-terminal domains of different sizes. ORs demonstrate high sequence identity in their TM domain (73%-76%) and in ILs (63%-66%) and large divergence in N-and C-terminal domains and ELs (34%-40% identity). ORs are activated by either endogenous peptides o...

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“…The aliphatic 6-hydroxyl group was first thought to interact with Tyr 326 (Mansour et al, 1997) or with Asn 230 (Pogozheva et al, 1998). Our group showed that the potency of morphine increased when this Asn 230 residue was replaced by a hydrophobic amino acid (Pil and Tytgat, 2001).…”

Section: Discussionmentioning

confidence: 99%

Serine 329 of the μ-Opioid Receptor Interacts Differently with Agonists

Pil

Tytgat²

2002

J Pharmacol Exp Ther

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To investigate the effect of the hydrophilic Ser amino acid in position 329 of the human -opioid receptor (hMORwt) on the potency of various agonists, we mutated this residue to Ala (hMORS329A). Taking advantage of the functional coupling of the opioid receptor with the heteromultimeric G-protein-coupled inwardly rectifying potassium channel (GIRK1/GIRK2), either the wild-type hMOR or the mutated receptor (hMORS329A) was functionally coexpressed with GIRK1 and GIRK2 channels together with a regulator of G-protein signaling (RGS4) in Xenopus laevis oocytes. The two-microelectrode voltageclamp technique was used to measure the opioid receptor activated GIRK1/GIRK2 channel responses. The potency of the peptide agonist [D-Ala 2 ,N-MePhe 4 ,Gly 5 -ol]-enkephalin (DAMGO) decreased as measured via hMORS329A, whereas the potency of nonpeptide agonists like morphine, fentanyl, and ␤-hydroxyfentanyl (R004333) increased via the mutated receptor. Our results are indicative for the existence of hydrophilic interactions between Ser 329 and DAMGO, thereby decreasing the potency of DAMGO via the mutated receptor, whereas hydrophobic interactions between the mutated receptor and the N-phenylethyl of morphine and fentanyl can explain the increased potency. We conclude that the hydroxyl group of Ser 329 is not involved in the formation of a hydrogen bond with the ␤-hydroxy group of fentanyl and that mutation of this residue to alanine caused dual effects depending on the nature of the ligand.

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Key Residues Defining the μ‐Opioid Receptor Binding Pocket: A Site‐Directed Mutagenesis Study

Cited by 125 publications

References 26 publications

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

Homology modeling of opioid receptor-ligand complexes using experimental constraints

Serine 329 of the μ-Opioid Receptor Interacts Differently with Agonists

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