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Titolo:
Mapping the agonist-binding site of GABA(B) type 1 subunit sheds light on the activation process of GABA(B) receptors
Autore:
Galvez, T; Prezeau, L; Milioti, G; Franek, M; Joly, C; Froestl, W; Bettler, B; Bertrand, HO; Blahos, J; Pin, JP;
Indirizzi:
CNRS, UPR9023, CCIPE, F-34094 Montpellier 5, France CNRS Montpellier France 5 UPR9023, CCIPE, F-34094 Montpellier 5, France Charles Univ, Lab Mol Physiol, Med Sch 3, Prague 2, Czech Republic CharlesUniv Prague Czech Republic 2 Med Sch 3, Prague 2, Czech Republic Acad Sci Czech Republ, Prague 2, Czech Republic Acad Sci Czech Republ Prague Czech Republic 2 , Prague 2, Czech Republic Novartis Pharma AG, TA Nervous Syst, CH-4002 Basel, Switzerland Novartis Pharma AG Basel Switzerland CH-4002 CH-4002 Basel, Switzerland Mol Simulat Inc, F-91893 Orsay, France Mol Simulat Inc Orsay France F-91893 Simulat Inc, F-91893 Orsay, France
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 52, volume: 275, anno: 2000,
pagine: 41166 - 41174
SICI:
0021-9258(200012)275:52<41166:MTASOG>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
METABOTROPIC GLUTAMATE RECEPTORS; PUTATIVE PHEROMONE RECEPTORS; CALCIUM-SENSING RECEPTOR; AMINO-TERMINAL DOMAIN; LIGAND-BINDING; MGLUR4 SUBTYPE; PROTEIN; IDENTIFICATION; EXPRESSION; CLONING;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
45
Recensione:
Indirizzi per estratti:
Indirizzo: Galvez, T CNRS, UPR9023, CCIPE, 141 Rue Cardonille, F-34094 Montpellier 5,France CNRS 141 Rue Cardonille Montpellier France 5 tpellier 5, France
Citazione:
T. Galvez et al., "Mapping the agonist-binding site of GABA(B) type 1 subunit sheds light on the activation process of GABA(B) receptors", J BIOL CHEM, 275(52), 2000, pp. 41166-41174

Abstract

The gamma -amino-n-butyric acid type B (GABA(B)) receptor is composed of two subunits, GABA(B)1 and GABA(B)2, belonging to the family 3 heptahelix receptors. These proteins possess two domains, a seven transmembrane core andan extracellular domain containing the agonist binding site. This binding domain is likely to fold like bacterial periplasmic binding proteins that are constituted of two lobes that close upon ligand binding. Here, using molecular modeling and site-directed mutagenesis, we have identified residues in the GABA(B)1 subunit that are critical for agonist binding and activation of the heteromeric receptor. Our data suggest that two residues (Ser(246)and Asp(471)) located within lobe I form H bonds and a salt bridge with carboxylic and amino groups of GABA, respectively, demonstrating the pivotal role of lobe I in agonist binding. Interestingly, our data also suggest that a residue within lobe II (Tyr(366)) interacts with the agonists in a closed form model of the binding domain, and its mutation into Ala converts theagonist baclofen into an antagonist. These data demonstrate the pivotal role played by the GABA(B)1 subunit in the activation of the heteromeric GABA(B) receptor and are-consistent with the idea that a closed state of the binding domain of family 3 receptors is required for their activation.

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Documento generato il 31/03/20 alle ore 09:13:48