PDBsum entry 8gss

Transferase

PDB id: 8gss

Contents

Protein chain

209 a.a. *

Ligands

SO4 ×2

GSH ×3

MES ×2

Waters ×650

* Residue conservation analysis

PDB id:

8gss

Name:

Transferase

Title:

Human glutathione s-transferase p1-1, complex with glutathione

Structure:

Glutathione s-transferase p1-1. Chain: a, b, c. Fragment: three intact monomers. Synonym: gstp1-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: placenta. Cellular_location: cytoplasm. Gene: gtp_human. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Dimer (from PDB file)

Resolution:

1.90Å R-factor: 0.193 R-free: 0.229

Authors:

A.Oakley,M.Parker

Key ref:

A.J.Oakley et al. (1997). The structures of human glutathione transferase P1-1 in complex with glutathione and various inhibitors at high resolution. J Mol Biol, 274, 84. PubMed id: 9398518 DOI: 10.1006/jmbi.1997.1364

Date:

14-Aug-97 Release date: 16-Sep-98

Protein chains

P09211  (GSTP1_HUMAN) -  Glutathione S-transferase P from Homo sapiens

Seq: 210 a.a.

Struc: 209 a.a.

Enzyme reactions

• Enzyme class: E.C.2.5.1.18 - glutathione transferase.
• Reaction: RX + glutathione = an S-substituted glutathione + a halide anion + H⁺

RX + glutathione (Bound ligand (Het Group name = GSH) corresponds exactly) = S-substituted glutathione + halide anion + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1006/jmbi.1997.1364

J Mol Biol 274:84 (1997)

PubMed id: 9398518

The structures of human glutathione transferase P1-1 in complex with glutathione and various inhibitors at high resolution.

A.J.Oakley, M.Lo Bello, A.Battistoni, G.Ricci, J.Rossjohn, H.O.Villar, M.W.Parker.

ABSTRACT

The human pi-class glutathione S-transferase (hGST P1-1) is a target for structure-based inhibitor design with the aim of developing drugs that could be used as adjuvants in chemotherapeutic treatment. Here we present seven crystal structures of the enzyme in complex with substrate (glutathione) and two inhibitors (S-hexyl glutathione and gamma-glutamyl- (S-benzyl)cysteinyl-D-phenylglycine). The binding of the modified glutathione inhibitor, gamma-glutamyl-(S-benzyl)cysteinyl-D-phenylglycine, has been characterized with the phenyl group stacking against the benzyl moiety of the inhibitor and making interactions with the active-site residues Phe8 and Trp38. The structure provides an explanation as to why this compound inhibits the pi-class GST much better than the other GST classes. The structure of the enzyme in complex with glutathione has been determined to high resolution (1.9 to 2.2 A) in three different crystal forms and at two different temperatures (100 and 288 K). In one crystal form, the direct hydrogen-bonding interaction between the hydroxyl group of Tyr7, a residue involved in catalysis, and the thiol group of the substrate, glutathione, is broken and replaced by a water molecule that mediates the interaction. The hydrogen-bonding partner of the hydroxyl group of Tyr108, another residue implicated in the catalysis, is space-group dependent. A high-resolution (2.0 A) structure of the enzyme in complex with S-hexyl glutathione in a new crystal form is presented. The enzyme-inhibitor complexes show that the binding of ligand into the electrophilic binding site does not lead to any conformational changes of the protein.

Selected figure(s)

Figure 3.
Figure 3. Schematic drawing of residues that interact with the substrates and inhibitors. (a) GSH (C2 form, 100 K) and (b) TER-117 (C2 form, 288 K). The key to the Figures is shown in part (a). These Figures were produced using the program LIGPLOT [Wallace et al 1995].

Figure 7.
Figure 7. Superposition of the active sites of the alpha-class hGST A1-1 [Sinning et al 1993], human mu-class GST M2-2 [Raghunathan et al 1994] and human hGST P1-1 crystal structures showing the fit of the inhibitor TER-117. The structures are colored yellow, green and mauve, respectively. The characteristic Mu-loop of the rat enzyme and the C-terminal helix α9 of the alpha-class enzyme are shown. Residues likely to collide with the phenyl ring of the inhibitor are highlighted. This Figure was generated with the program package INSIGHT II (Molecular Simulations Inc., San Diego, CA, USA.).

The above figures are reprinted by permission from Elsevier: J Mol Biol (1997, 274, 84-0) copyright 1997.

Figures were selected by an automated process.