2C3Q

Human glutathione-S-transferase T1-1 W234R mutant, complex with S- hexylglutathione

Summary for 2C3Q

• Entry DOI: 10.2210/pdb2c3q/pdb
• Related: 2C3N 2C3T
• Descriptor: GLUTATHIONE S-TRANSFERASE THETA 1, S-HEXYLGLUTATHIONE, IODIDE ION, ... (4 entities in total)
• Functional Keywords: transferase, glutathione, glutathione transferase, t1-1, polymorphism
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 4
• Total formula weight: 118704.26

Authors

Tars, K.,Larsson, A.-K.,Shokeer, A.,Olin, B.,Mannervik, B.,Kleywegt, G.J. (deposition date: 2005-10-11, release date: 2005-11-30, Last modification date: 2023-12-13)

Primary citation

Tars, K.,Larsson, A.-K.,Shokeer, A.,Olin, B.,Mannervik, B.,Kleywegt, G.J.
Structural Basis of the Suppressed Catalytic Activity of Wild-Type Human Glutathione Transferase T1-1 Compared to its W234R Mutant.
J.Mol.Biol., 355:96-, 2006

PubMed Abstract: 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.

PubMed: 16298388
DOI: 10.1016/J.JMB.2005.10.049

Experimental method

X-RAY DIFFRACTION (1.85 Å)