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Titolo:
A beta-strand in the gamma(2) subunit lines the benzodiazepine binding site of the GABA(A) receptor: Structural rearrangements detected during channel gating
Autore:
Teissere, JA; Czajkowski, C;
Indirizzi:
Univ Wisconsin, Dept Physiol, Madison, WI 53706 USA Univ Wisconsin Madison WI USA 53706 , Dept Physiol, Madison, WI 53706 USA Univ Wisconsin, Neurosci Training Program, Madison, WI 53706 USA Univ Wisconsin Madison WI USA 53706 aining Program, Madison, WI 53706 USA
Titolo Testata:
JOURNAL OF NEUROSCIENCE
fascicolo: 14, volume: 21, anno: 2001,
pagine: 4977 - 4986
SICI:
0270-6474(20010715)21:14<4977:ABITGS>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
MEMBRANE-SPANNING SEGMENT; AMINOBUTYRIC ACID(A) RECEPTORS; ALPHA-SUBUNIT; A RECEPTORS; RESIDUES; IDENTIFICATION; ACCESSIBILITY; LIGANDS; ORIENTATION; MODULATION;
Keywords:
benzodiazepine; binding site; allostery; ligand-gated ion channel; GABA; GABA(A) receptor; substituted cysteine accessibility method; Xenopus oocytes; secondary structure;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
30
Recensione:
Indirizzi per estratti:
Indirizzo: Czajkowski, C Univ Wisconsin, Dept Physiol, Room 197 MSC,1300 Univ Ave, Madison, WI 53706 USA Univ Wisconsin Room 197 MSC,1300 Univ Ave Madison WI USA 53706
Citazione:
J.A. Teissere e C. Czajkowski, "A beta-strand in the gamma(2) subunit lines the benzodiazepine binding site of the GABA(A) receptor: Structural rearrangements detected during channel gating", J NEUROSC, 21(14), 2001, pp. 4977-4986

Abstract

Benzodiazepines (BZDs) exert their effects in the CNS by binding to a modulatory site on GABA(A) receptors. Individual amino acids have been implicated in BZD recognition and modulation of the GABA(A) receptor, but the secondary structure of the amino acids contributing to the BZD binding site has not been elucidated. In this report we used the substituted cysteine accessibility method to understand the structural dynamics of a region of the GABA(A) receptor implicated in BZD binding, gamma (2)Y72-gamma (2)Y83. Each residue within this region was mutated to cysteine and expressed with wild-type alpha (1) and beta (2) subunits in Xenopus oocytes. Methanethiosulfonate(MTS) reagents were used to modify covalently the engineered cysteines, and the subsequent effects on BZD modulation of the receptor were monitored functionally by two-electrode voltage clamp. We identified an alternating pattern of accessibility to sulfhydryl modification, indicating that the region gamma (2)T73-gamma (2)T81 adopts a beta -strand conformation. By monitoring the ability of BZD ligands to impede the covalent modification of accessible cysteines, we also identified two residues within this region, gamma (2)A79 and gamma (2)T81, that line the BZD binding site. Sulfhydryl modification of gamma (2)A79C or gamma (2)T81C allosterically shifts the GABA EC50of the receptor, suggesting that certain MTS compounds may act as tetheredagonists at the BZD binding site. Last, we present structural evidence that a portion of the BZD binding site undergoes a conformational change in response to GABA binding and channel gating (opening and desensitization). These data represent an important step in understanding allosteric communication in ligand-gated ion channels.

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Documento generato il 29/03/20 alle ore 14:27:16