2c3q

From Proteopedia

Revision as of 16:58, 18 December 2007

HUMAN GLUTATHIONE-S-TRANSFERASE T1-1 W234R MUTANT, COMPLEX WITH S-HEXYLGLUTATHIONE

Overview

The crystal structures of wild-type human theta class, glutathione-S-transferase (GST) T1-1 and its W234R mutant, where Trp234, was replaced by Arg, were solved both in the presence and absence of, S-hexyl-glutathione. The W234R mutant was of interest due to its, previously observed enhanced catalytic activity compared to the wild-type, enzyme. GST T1-1 from rat and mouse naturally contain Arg in position 234, with correspondingly high catalytic efficiency. The overall structure of, GST T1-1 is similar to that of GST T2-2, as expected from their 53%, sequence identity at the protein level. Wild-type GST T1-1 has the, side-chain of Trp234 occupying a significant portion of the active site., This bulky residue prevents efficient binding of both glutathione and, hydrophobic substrates through steric hindrance. The wild-type GST T1-1, crystal structure, obtained from co-crystallization experiments with, glutathione and its derivatives, showed no electron density for the, glutathione ligand. However, the structure of GST T1-1 mutant W234R showed, clear electron density for S-hexyl-glutathione after co-crystallization., In contrast to Trp234 in the wild-type structure, the side-chain of Arg234, in the mutant does not occupy any part of the substrate-binding site., Instead, Arg234 is pointing in a different direction and, in addition, interacts with the carboxylate group of glutathione. These findings, explain our earlier observation that the W234R mutant has a markedly, improved catalytic activity with most substrates tested to date compared, to the wild-type enzyme. GST T1-1 catalyzes detoxication reactions as well, as reactions that result in toxic products, and our findings therefore, suggest that humans have gained an evolutionary advantage by a partially, disabled active site.

About this Structure

2C3Q is a Single protein structure of sequence from Homo sapiens with IOD and GTX as ligands. Active as Glutathione transferase, with EC number 2.5.1.18 Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Structural basis of the suppressed catalytic activity of wild-type human glutathione transferase T1-1 compared to its W234R mutant., Tars K, Larsson AK, Shokeer A, Olin B, Mannervik B, Kleywegt GJ, J Mol Biol. 2006 Jan 6;355(1):96-105. Epub 2005 Nov 8. PMID:16298388

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