Identification of transmembrane domain 6 &amp; 7 residues that contribute to the binding pocket of the urotensin II receptor

Holleran, Brian J.; Domazet, Ivana; Beaulieu, Marie-Ève; Li, Yan; Guillemette, Gaétan; Lavigne, Pierre; Escher, Emanuel; Leduc, Richard

doi:10.1016/j.bcp.2009.01.013

Cited by 11 publications

(15 citation statements)

References 35 publications

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“…Transmembrane domain VI and transmembrane domain VII are also both involved in the formation of the binding pocket, with the residue W278 (6.54) serving as a focal point of interaction. In summary, the UT receptor appears to be quite similar to previously described class A GPCRs (49). The information that is known to date about the structure of UT is rather piecemeal.…”

Section: Uii-ut Interactionsupporting

confidence: 66%

Role of urotensin II in health and disease

Ross

McKendy

Giaid

2010

American Journal of Physiology-Regulatory, Integrative and Comp

128

107

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Urotensin II (UII) is an 11 amino acid cyclic peptide originally isolated from the goby fish. The amino acid sequence of UII is exceptionally conserved across most vertebrate taxa, sharing structural similarity to somatostatin. UII binds to a class of G protein-coupled receptor known as GPR14 or the urotensin receptor (UT). UII and its receptor, UT, are widely expressed throughout the cardiovascular, pulmonary, central nervous, renal, and metabolic systems. UII is generally agreed to be the most potent endogenous vasoconstrictor discovered to date. Its physiological mechanisms are similar in some ways to other potent mediators, such as endothelin-1. For example, both compounds elicit a strong vascular smooth muscle-dependent vasoconstriction via Ca 2ϩ release. UII also exerts a wide range of actions in other systems, such as proliferation of vascular smooth muscle cells, fibroblasts, and cancer cells. It also 1) enhances foam cell formation, chemotaxis of inflammatory cells, and inotropic and hypertrophic effects on heart muscle; 2) inhibits insulin release, modulates glomerular filtration, and release of catecholamines; and 3) may help regulate food intake and the sleep cycle. Elevated plasma levels of UII and increased levels of UII and UT expression have been demonstrated in numerous diseased conditions, including hypertension, atherosclerosis, heart failure, pulmonary hypertension, diabetes, renal failure, and the metabolic syndrome. Indeed, some of these reports suggest that UII is a marker of disease activity. As such, the UT receptor is emerging as a promising target for therapeutic intervention. Here, a concise review is given on the vast physiologic and pathologic roles of UII.UT receptor; somatostatin; human; experimental animals; autocrine/paracrine UROTENSIN II (UII) was initially isolated from the urophysis of the goby fish (Gillichthys mirabilis) (97). The peptide was subsequently isolated from the white sucker (Catostomus commersoni) and the carp (Cyprinus carpio). Although there were variations in the amino acid sequence near the amino terminus, in both species the UII molecule retained the COOH-terminal cyclic sequence: -Cys

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Section: Uii-ut Interactionsupporting

confidence: 66%

Role of urotensin II in health and disease

Ross

McKendy

Giaid

2010

American Journal of Physiology-Regulatory, Integrative and Comp

128

107

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“…Out of the top five models predicted by I-TASSER, we selected the model that was the most appropriate to allow the insertion of UII in the rUT receptor binding pocket (model 1, C-score = 0.24). Previous modeling done by us was used as the basis for the initial UII peptide orientation within the binding pocket [34,42]. The GROMACS software suite [43] was used with the OPLS/AA forcefield [44][45][46] and GBSA implicit solvent model [47] to perform potential energy minimization and a molecular dynamic simulation of the UII/rUT receptor complex.…”

Section: Molecular Modelingmentioning

confidence: 99%

“…Two criteria are used to determine whether engineered cysteines are positioned at the surface of the bindingsite pocket: (i) the reaction with the MTSEA reagent alters binding irreversibly and (ii) the reaction is retarded by the presence of the ligand. This approach has been used by us and others to identify residues that line the surface of GPCR binding-site pockets [29][30][31][32][33][34][35][36][37]. Indeed, using SCAM analysis, we have previously identified eleven MTSEA-sensitive residues in TM3, TM4, TM5, TM6 and TM7 of the rat UT receptor (rUT receptor) [34,36] that make up that receptor's binding pocket.…”

Section: Introductionmentioning

confidence: 99%

“…This approach has been used by us and others to identify residues that line the surface of GPCR binding-site pockets [29][30][31][32][33][34][35][36][37]. Indeed, using SCAM analysis, we have previously identified eleven MTSEA-sensitive residues in TM3, TM4, TM5, TM6 and TM7 of the rat UT receptor (rUT receptor) [34,36] that make up that receptor's binding pocket. In this study, we report the identification of residues within TM1 and TM2 that forms the UT binding pocket and we propose a complete molecular model of the ligand-binding cavity of the rUT receptor.…”

Section: Introductionmentioning

confidence: 99%

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Identification of transmembrane domain 1 & 2 residues that contribute to the formation of the ligand-binding pocket of the urotensin-II receptor

Sainsily

Cabana

Holleran

et al. 2014

Biochemical Pharmacology

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The vasoactive urotensin-II (UII), a cyclic undecapeptide widely distributed in cardiovascular, renal and endocrine systems, specifically binds the UII receptor (UT receptor), a G protein-coupled receptor (GPCR). The involvement of this receptor in numerous pathophysiological conditions including atherosclerosis, heart failure, hypertension, renal impairment and diabetes potentially makes it an interesting therapeutic target. To elucidate how UII binds the UT receptor through the identification of specific residues in transmembrane domains (TM) one (TM1) and two (TM2) that are involved in the formation of the receptor's binding pocket, we used the substituted-cysteine accessibility method (SCAM). Each residue of TM1 (V49((1.30)) to M76((1.57))) and TM2 (V88((2.41)) to H117((2.70))) was mutated, one by one, to a cysteine. The resulting mutants were then expressed in COS-7 cells and subsequently treated with the sulfhydryl-specific alkylating agent methanethiosulfonate-ethylammonium (MTSEA). MTSEA treatment resulted in a significant binding inhibition of (125)I-UII to mutant I54C((1.35)) in TM1 and mutants Y100C((2.53)), S103C((2.56)), F106C((2.59)), I107C((2.60)), T110C((2.63)) and Y111C((2.64)) in TM2. These results identify key structural residues in TM1 and TM2 that participate in the formation of the UT receptor binding pocket. Together with previous SCAM analysis of TM3, TM4, TM5, TM6 and TM7, these results have led us to identify residues within all 7 TMs that participate in UT's binding pocket and have enabled us to propose a model of this receptor's orthosteric binding site.

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“…This contact may participate to the primary recognition process of UT by UII and thus to the selectivity of the ligand, or it may constitute an allosteric site of interaction. By using the substituted-cysteine accessibility method (Javitch et al, 2002), it was recently demonstrated that several TMD3, TMD4, TMD5, TMD6, and TMD7 residues of rat UT participate to the formation of the receptor binding pocket (Holleran et al, 2009;Sainsily et al, 2013). However, there are still numerous unsolved questions regarding the molecular interactions between UT and its natural ligands.…”

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confidence: 99%