Linked Life Data

16754677

Source:http://linkedlifedata.com/resource/pubmed/id/16754677

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
34
pubmed:dateCreated
2006-8-21
pubmed:abstractText
gamma-Aminobutyric acid, type A (GABA(A)) receptors, of which the GABA(C) receptor family is a subgroup, are members of the Cys loop family of neurotransmitter receptors. Homology modeling of the extracellular domain of these proteins has revealed many molecular details, but it is not yet clear how GABA is orientated in the binding pocket. Here we have examined the role of arginine residues that the homology model locates in or close to the binding site of the GABA(C) receptor (Arg-104, Arg-170, Arg-158, and Arg-249) using mutagenesis and functional studies. The data suggest that Arg-158 is critical for GABA binding and/or function; substitution with Lys, Ala, or Glu resulted in nonfunctional receptors, and modeling placed the carboxylate of GABA within 3A of this residue. Substitution of Arg-104 with Ala or Glu resulted in >10,000-fold increases in EC(50) values compared with wild type receptors, and modeling indicated a role of this residue both in binding GABA and in the structure of the binding pocket. Substitution of Arg-170 with Asp or Ala yielded nonfunctional receptors, whereas Lys caused an approximately 10-fold increase in EC(50). Arg-249 was substituted with Ala, Glu, or Asp with relatively small ( approximately 4-30-fold) changes in EC(50). These and data from other residues that the model suggested could interact with GABA (His-105, Ser-168, and Ser-243) support a location for GABA in the binding site with its carboxylate pincered between Arg-158 and Arg-104, with Arg-104, Arg-170, and Arg-249 contributing to the structure of the binding pocket through salt bridges and/or hydrogen bonds.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
25
pubmed:volume
281
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
24455-61
pubmed:dateRevised
2009-1-7
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
Locating the carboxylate group of GABA in the homomeric rho GABA(A) receptor ligand-binding pocket.
pubmed:affiliation
Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't