Linked Life Data

21530062

Source:http://linkedlifedata.com/resource/pubmed/id/21530062

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2-3
pubmed:dateCreated
2011-5-16
pubmed:abstractText
A C-terminal helix (?9) adjacent to the active site on each subunit is a structural feature unique to the alpha isoform of glutathione transferases which contributes to the catalytic and ligandin functions of the enzyme. The ionisation state of Tyr-9, a residue critical to catalysis, influences ?9 dynamics, although the mechanism is poorly understood. In this study, isothermal titration calorimetry was used to probe the binding energetics of G-site (glutathione and glutathione sulfonate) and H-site (ethacrynic acid) ligands to wild-type and a Y9F mutant of human glutathione transferase A1-1. Although previous studies have reported a favourable entropic component to the binding of conjugates occupying both sites, our data reveal that ligand binding is enthalpically driven when either the G- or H-site is occupied independently. Also, heat capacity changes demonstrate that ?9 is fully localised by H-site but not G-site occupation. The Tyr-9 hydroxyl group contributes significantly to ligand binding energetics, although the effect differs between the two binding sites. G-site binding is made slightly enthalpically more favourable and entropically less favourable by the Y9F mutation. Binding to the H-site is more dramatically affected, with the K(d) for ethacrynic acid increasing 5 fold despite a more favourable ?S. The heat capacity change is more negative for G-site binding in the absence of the Tyr-9 hydroxyl (??C(p)=-0.73 kJ mol(-1) K(-1)), but less negative for H-site binding to the Y9F mutant (??C(p)=0.63 kJ mol(-1) K(-1)). This suggests that the relationship between Tyr-9 and ?9 is not independent of the ligand. Rather, Tyr-9 appears to function in orienting the ligand optimally for ?9 closure.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
1873-4200
pubmed:author
pubmed:copyrightInfo
Copyright © 2011 Elsevier B.V. All rights reserved.
pubmed:issnType
Electronic
pubmed:volume
156
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
153-8
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Energetics of ligand binding to human glutathione transferase A1-1: Tyr-9 associated localisation of the C-terminal helix is ligand-dependent.
pubmed:affiliation
Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, South Africa.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't