Identification of the amino acid residues involved in selective agonist binding in the first extracellular loop of the δ‐ and μ‐opioid receptors

Fukuda, Kazuhiko; Terasako, Kiyoshi; Kato, Shigeshisa; Mori, Kenjiro

doi:10.1016/0014-5793(95)01034-c

Cited by 38 publications

(20 citation statements)

References 23 publications

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“…First, deletion of five amino acids that extended from the TM5 or TM6 might disturb the structure of the receptor or arrangement of these two TM domains. Studies with several GPCRs and opioid receptor chimera studies have indicated that interaction among TM domains results in the formation of ligand binding sites (Fukuda et al, 1995;Wess, 1998). However, the deletion of i3-1 and i3-5 domains simultaneously disturbed the binding of DAMGO, morphine, and PL017, which has been demonstrated to have overlapping but different binding domains within the receptor .…”

Section: Discussionmentioning

confidence: 99%

Ligand-Selective Activation of μ-Opioid Receptor: Demonstrated with Deletion and Single Amino Acid Mutations of Third Intracellular Loop Domain

Chaipatikul

Loh²,

Law³

2003

J Pharmacol Exp Ther

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The mechanism for the differential regulation of the -opioid receptor by agonists is investigated by identifying the receptor domains used to define the relative efficacies of three -opioid with Ala reduced the potency of DAMGO but not that of morphine PL017. Meanwhile, mutation of Thr 279 to Ala increased the potencies of morphine and PL017 but not that of DAMGO. The I278A mutation decreased the DAMGO coupling efficiency but increased the PL017 coupling efficiency. The R280A mutation resulted in the increase in PL017 potency and coupling efficiency without altering those of DAMGO and morphine. Thus, these mutation studies suggested that the activation of -opioid receptor and interaction between the critical domains such as RRITR within third intracellular loop and the G proteins are agonist-selective.Opioid receptors are members of the G protein-coupled receptors (GPCRs) (Wess, 1998). Mutational analyses of many members of GPCR family provide evidence that the second and third intracellular loops and the C-terminal tails are involved in the receptor/G protein coupling (for review, see Helmreich and Hofmann, 1996). However, the consensus sequence in the receptor/G protein coupling has yet to be identified. Possibly, in addition to its primary sequence, a secondary structure of the receptor, i.e., the amphipatic ␣-helix is a determinant for G proteins and receptor interaction. Sequence alignment revealed that BBXXB (B stands for basic amino acids and X is any amino acid) sequence was commonly found in the regions of GPCRs critical for G protein interaction. Detailed studies further suggested that the basic amino acids in BBXXB motif are crucial for activating Gprotein. In the human platelet-activating factor (PAF) receptor, mutation in the BBXXB motif resulted in mutants with low-affinity binding for PAF and less effective in mediating phosphatidylinositol hydrolysis (Parent et al., 1996). Use of peptides corresponding to the third intracellular loop of the ␦-opioid receptor, Georgoussi et al. (1997) and Merkouris et al. (1996) demonstrated the importance of this motif in the opioid receptor/G protein interaction. The basic amino acids within this motif have been suggested to form a polar pocket interacting with motifs in other domains of the GPCR, such as the conserved (D/E)RY motif at the N terminus of the second intracellular loop, thus stabilizing the receptor in the inactive states. Binding of the agonist results in transmembrane (TM) movement, thus disrupting such interaction and resulted in the receptor activation. This hypothesis is supported by studies with the mutation of amino acids within this region and the Ala insertion studies that resulted in constitutive activities of the muscarinic receptor (Liu et al

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Section: Discussionmentioning

confidence: 99%

Ligand-Selective Activation of μ-Opioid Receptor: Demonstrated with Deletion and Single Amino Acid Mutations of Third Intracellular Loop Domain

Chaipatikul

Loh²,

Law³

2003

J Pharmacol Exp Ther

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“…The opioid binding pocket and the G protein-coupling domain were originally assessed by chimera and mutagenesis approaches (for review, see Law and Loh, 1999;Chavkin et al, 2001). 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).…”

Section: A Mor-1mentioning

confidence: 99%

Mu Opioids and Their Receptors: Evolution of a Concept

2013

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“…[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. 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.…”

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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Identification of the amino acid residues involved in selective agonist binding in the first extracellular loop of the δ‐ and μ‐opioid receptors

Cited by 38 publications

References 23 publications

Ligand-Selective Activation of μ-Opioid Receptor: Demonstrated with Deletion and Single Amino Acid Mutations of Third Intracellular Loop Domain

Ligand-Selective Activation of μ-Opioid Receptor: Demonstrated with Deletion and Single Amino Acid Mutations of Third Intracellular Loop Domain

Mu Opioids and Their Receptors: Evolution of a Concept

Homology modeling of opioid receptor-ligand complexes using experimental constraints

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