Selectivity of μ-opioid receptor determined by interfacial residues near third extracellular loop

Bonner, G. Gregg; Meng, Fan; Akil, Huda

doi:10.1016/s0014-2999(00)00578-1

Cited by 50 publications

(47 citation statements)

References 16 publications

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“…An alternative possibility is that sterically determined interactions dictate ligand specificity in this system, and this idea may be supported, at least for group I, by our finding that the AgrC-I S107A,S116A double mutant demonstrated only moderately reduced activation by AIP-I when compared with the wild type receptor. A similar result can be found in a study of the mammalian -opioid receptor, a polytopic G protein-coupled receptor that also senses a peptide ligand (24). When an amino acid near its third extracellular loop, tryptophan, was replaced with the corresponding residue of the ␦-opioid receptor (leucine) or a charged residue (lysine), a switch in specificity toward ␦-opioids was observed, suggesting that the interaction between specificity determinants on ligand and receptor did not depend on polarity and instead involved steric hindrance.…”

Section: Discussionsupporting

confidence: 80%

Identification of Ligand Specificity Determinants in AgrC, the Staphylococcus aureus Quorum-sensing Receptor

Geisinger

George

Muir

et al. 2008

Journal of Biological Chemistry

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Activation of the agr system, a major regulator of staphylococcal virulence, is initiated by the binding of a specific autoinducing peptide (AIP) to the extracellular domain of AgrC, a classical receptor histidine protein kinase. There are four known agr specificity groups in Staphylococcus aureus, and we have previously localized the determinant of AIP receptor specificity to the C-terminal half of the AgrC sensor domain. We have now identified the specific amino acid residues that determine ligand activation specificity for agr groups I and IV, the two most closely related. Comparison of the AgrC-I and AgrC-IV sequences revealed a set of five divergent residues in the region of the second extracellular loop of the receptor that could be responsible. Accordingly, we exchanged these residues between AgrC-I and AgrC-IV and tested the resulting constructs for activation by the respective AIPs, measuring activation kinetics with a transcriptional fusion of blaZ to the principal agr promoter, P3. Exchange of all five residues caused a complete switch in receptor specificity. Replacement of two of the AgrC-IV residues by the corresponding residues in AgrC-I caused the receptor to be activated by AIP-I nearly as well as the wild type AgrC-I receptor. Replacement of two different AgrC-I residues by the corresponding AgrC-IV residues broadened receptor recognition specificity to include both AIPs. Various types of intermediate activity were observed with other replacement mutations. Preliminary characterization of the AgrC-I-AIP-I interaction suggests that ligand specificity may be sterically determined.

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Section: Discussionsupporting

confidence: 80%

Identification of Ligand Specificity Determinants in AgrC, the Staphylococcus aureus Quorum-sensing Receptor

Geisinger

George

Muir

et al. 2008

Journal of Biological Chemistry

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“…Chimeras involving mu/ delta and mu/kappa receptors implicate the extracellular loops 1 and 3 and TMs 2, 6, and 7 in mu ligand binding (Fukuda et al, 1995;Wang et al, 1995;Watson et al, 1996;Dietrich et al, 1998;Seki et al, 1998). A number of individual residues involved with binding have been identified by site-directed mutagenesis (Xue et al, 1994;Minami et al, 1996;Xu et al, 1999a;Zhang et al, 1999;Bonner et al, 2000;Ulens et al, 2000). The domains and residues involved in G protein coupling, mu agonist-induced receptor phosphorylation, internalization, and desensitization have also been described using similar approaches Law and Loh, 1999;Chavkin et al, 2001).…”

Section: A Mor-1mentioning

confidence: 99%

Mu Opioids and Their Receptors: Evolution of a Concept

2013

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“…51 Variable binding pocket residues confer selectivity. For example, Lys108 in EL1 of DOR prevents binding of the m -selective DAMGO 52 ; residues from EL2 and EL3 confer the selectivity of dynorphin to KOR 39 , 53-55 ; and variable residues from EL3 and adjacent helices, particularly Lys303(6.58), Trp318(7.35), and His319(7.73) of MOR and the corresponding Trp284(6.58) and Leu300(7.35) and His301(7.36) of DOR are important for selective binding of morphine, DAMGO, and fentanyl analogs to MOR, [56][57][58] and of DPDPE, SNC80, and TAN67 to DOR. 37 , 59 , 60 Glu297(6.58) in KOR is involved in binding of norBNI.…”

Section: Experimental Studies Of Receptor-ligand Interactionsmentioning

confidence: 99%

“…In MOR, Trp318(7.35) forms an aromatic interaction with Phe3 of JOM6, supporting the important role of Trp318(7.35) in peptide binding to MOR. 56 Similarly, in KOR Tyr312(7.35) forms an aromatic interaction with Phe3 of MP16. The smaller size of the binding pocket in KOR relative to that in MOR, owing to extra residues inserted into EL2, prevents the binding of tetrapeptides with bulkier side chain substitutions in the Phe3 position.…”

Section: E441mentioning

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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Selectivity of μ-opioid receptor determined by interfacial residues near third extracellular loop

Cited by 50 publications

References 16 publications

Identification of Ligand Specificity Determinants in AgrC, the Staphylococcus aureus Quorum-sensing Receptor

Identification of Ligand Specificity Determinants in AgrC, the Staphylococcus aureus Quorum-sensing Receptor

Mu Opioids and Their Receptors: Evolution of a Concept

Homology modeling of opioid receptor-ligand complexes using experimental constraints

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