Application of the message-address concept to the docking of naltrexone and selective naltrexone-derived opioid antagonists into opioid receptor models

Metzger, Thomas; Paterlini, Marta; Portoghese, Philip S.; Ferguson, David M.

doi:10.1007/bf02532369

Cited by 78 publications

(110 citation statements)

References 32 publications

Supporting

Mentioning

104

Contrasting

Unclassified

Order By: Relevance

“…Computational Models for KOP Receptor Binding. Computational models have been used to describe KOP receptor binding and selectivity for KOP agonists (Metzger et al, 1996;Subramanian et al, 1998;Wan et al, 2000;Iadanza et al, 2002;Holzgrabe and Brandt, 2003). It has been proposed that the Asp138 carboxylate in TM III forms a salt bridge with the protonated amine of arylacetamides and benzomorphans, and a hydrophobic pocket consisting of Tyr312, Leu224, Leu295, and Ala298 side chains hosts the phenyl ring of arylacetamides.…”

Section: B Proposed Binding Interactions With -Opioid Receptorsmentioning

confidence: 99%

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

2011

View full text Add to dashboard Cite

Section: B Proposed Binding Interactions With -Opioid Receptorsmentioning

confidence: 99%

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

2011

View full text Add to dashboard Cite

“…These opioid receptors are coupled through pertussis-toxin sensitive G proteins to affect a variety of effectors [for a review, (8)]. Several groups have constructed molecular models of opioid receptors [for example, (9)(10)(11)(12)]. …”

mentioning

confidence: 99%

The Seventh Transmembrane Domains of the δ and κ Opioid Receptors Have Different Accessibility Patterns and Interhelical Interactions

Campillo

Pardo

et al. 2005

Biochemistry

View full text Add to dashboard Cite

We applied the substituted cysteine accessibility method (SCAM) to map the residues of the transmembrane helices (TMs) 7 of δ and κ opioid receptors (δOR and κOR) that are on wateraccessible surface of the binding-site crevices. Twenty five consecutive residues (except C7.38) in the TMs7 were mutated to Cys, one at a time, and each mutant was expressed in HEK 293 cells. Most mutants displayed similar binding affinity for [ 3 H]diprenorphine, an antagonist, as the wildtypes. Pretreatment with (2-aminoethyl) methanethiosulfonate (MTSEA) inhibited [ 3 H] diprenorphine binding to eight δOR and eight κOR mutants. All mutants except δOR L7.52(317)C were protected by naloxone from MTSEA effect, indicating that the side chains of V7.31(296), A7.34 (299), I7.39(304), L7.41(306), G7.42(307), P7.50(315) and Y7.53(318) of δOR and S7.34(311), F7.37(314), I7.39(316), A7.40(317), L7.41(318), G7.42(319), Y7.43(320) and N7.49(326) of κOR are on water-accessible surface of the binding pockets. Combining the SCAM data with rhodopsinbased molecular models of the receptors led to the following conclusions. i) The residues of the extracellular portion of TM7 predicted to face TM1 are sensitive to MTSEA in κOR, but are not in δOR. Thus, TM1 may be closer to TM7 in δOR than in κOR. ii) MTSEA-sensitive mutants start at position 7.31(296) in δOR and at 7.34(311) in κOR, suggesting that TM7 in δOR may have an additional helical turn (from 7.30 to 7.33). iii) There is a conserved H-bond network linking D2.50 of the NLxxxD motif in TM2 with W6.48 of the CWxP motif in TM6. iv) The NPxxY motif in TM7 interacts with TM2, TM6, and helix 8 to maintain receptors in inactive states. To the best of our knowledge, this represents the first such comparison of the structures of two highly homologous GPCRs.More than one thousand G protein-coupled receptors (GPCRs) are present in the human genome. GPCRs play important roles in physiological functions, including smell, taste, light perception, neurotransmission, functions of endocrine and exocrine glands and immune functions. In addition, GPCRs are targets of numerous clinically used drugs. It is, therefore, of great interests to understand their structures at the molecular level. Based on structural characteristics, GPCRs are classified into multiple families and the rhodopsin family is by far the largest in number. To date, rhodopsin is the only GPCR of which high-resolution crystal *Address correspondence to: Dr. Lee-Yuan Liu-Chen, Department of Pharmacology, Temple University School of Medicine, 3420 N. Broad St., Philadelphia, PA 19140, phone: (215) 707−4188; fax: (215) 707−7068; e-mail: E-mail: lliuche@temple.edu. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2009 June 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript structures have been elucidated (1-3). Rhodopsin has an extracellular N-terminal domain, seven transmembrane helices (TMs) connected by alternating intracellular and extracellular hydrophilic loops and an in...

show abstract

“…Models for G protein-linked receptors (Metzger et al, 1996) were used to position the putative extracellular domains of the /1 receptor that were exchanged with corresponding regions of AT! receptors.…”

Section: Resultsmentioning

confidence: 99%

“…In the present study, we have investigated the contribution of the N-terminal domain and of the three extracellular loops of the ji-opioid receptor in the structural organization of the ligand binding site by using chimenc~.t-opioid/type I angiotensin II (ATI) receptors in which swapped sequences were predicted to be strictly extracellular (Metzger et al, 1996). Our choice of the ATI receptor was based on the following: (a) The different binding properties of the two receptors may yield more clear-cut results than when using 6-or Kopioid receptors, (b) there is a similar amino acid sequence divergence between extracellular regions of ji and ATI and~i and 5 or K receptors, and (c) the length of angiotensin is similar to that of endogenous opioid peptides.…”

mentioning

confidence: 99%

Implication of the First and Third Extracellular Loops of the μ‐Opioid Receptor in the Formation of the Ligand Binding Site: A Study Using Chimeric μ‐Opioid/Angiotensin Receptors

Dietrich

Gaibelet

Capeyrou

et al. 1998

Journal of Neurochemistry

View full text Add to dashboard Cite

Recent studies on chimeric~i/6-, /1/K-and 6/ K-opioid receptors have suggested that extracellular loops of the receptors were involved in the discriminatory binding of selective ligands by controlling their entry into the transmembrane binding site. Since homochimeric opioid receptors are mostly informative in terms of selectivity, the role of extracellular loops was examined here by studying heterochimeric~.treceptors where the totality or parts of extracellular loops were replaced by the corresponding regions of the receptor for angiotensin II. Chimeric~sreceptors with extracellular loop ELi or EL3 originating from the angiotensin receptor had 100-fold decreased affinities for opioids; the length of the first extracellular loop, which is one residue longer in angiotensin than~receptors, was shown to be responsible for this situation. Substitution of the~.t receptor second extracellular loop by that of the angiotensin receptor diminished by~10-fold the affinities for opioids. Since all chimeras had altered affinitiesfor selective and nonselective ligands, we propose that extracellular domains of the ,u receptor, particularly the first and third loops, constrain the relative positioning of the connected transmembrane domains where selective as well as nonselective contact points form the opioid binding site.

show abstract

Application of the message-address concept to the docking of naltrexone and selective naltrexone-derived opioid antagonists into opioid receptor models

Cited by 78 publications

References 32 publications

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

The Seventh Transmembrane Domains of the δ and κ Opioid Receptors Have Different Accessibility Patterns and Interhelical Interactions

Implication of the First and Third Extracellular Loops of the μ‐Opioid Receptor in the Formation of the Ligand Binding Site: A Study Using Chimeric μ‐Opioid/Angiotensin Receptors

Contact Info

Product

Resources

About