PDBsum entry 1k3y

Transferase

PDB id: 1k3y

Contents

Protein chain

221 a.a. *

Ligands

GTX ×2

GOL ×3

Waters ×602

* Residue conservation analysis

PDB id:

1k3y

Name:

Transferase

Title:

Crystal structure analysis of human glutathione s-transferase with s- hexyl glutatione and glycerol at 1.3 angstrom

Structure:

Glutathione s-transferase a1. Chain: a, b. Synonym: gsta1-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Dimer (from PQS)

Resolution:

1.30Å R-factor: 0.137 R-free: 0.205

Authors:

I.Le Trong,R.E.Stenkamp,C.Ibarra,W.M.Atkins,E.T.Adman

Key ref:

I.Le Trong et al. (2002). 1.3-A resolution structure of human glutathione S-transferase with S-hexyl glutathione bound reveals possible extended ligandin binding site. Proteins, 48, 618-627. PubMed id: 12211029 DOI: 10.1002/prot.10162

Date:

04-Oct-01 Release date: 30-Oct-02

Protein chains

P08263  (GSTA1_HUMAN) -  Glutathione S-transferase A1 from Homo sapiens

Seq: 222 a.a.

Struc: 221 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 (Bound ligand (Het Group name = GTX) matches with 76.92% similarity) + glutathione = S-substituted glutathione + halide anion + H(+)

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

Added reference

DOI no: 10.1002/prot.10162

Proteins 48:618-627 (2002)

PubMed id: 12211029

1.3-A resolution structure of human glutathione S-transferase with S-hexyl glutathione bound reveals possible extended ligandin binding site.

I.Le Trong, R.E.Stenkamp, C.Ibarra, W.M.Atkins, E.T.Adman.

ABSTRACT

Cytosolic glutathione S-transferases (GSTs) play a critical role in xenobiotic binding and metabolism, as well as in modulation of oxidative stress. Here, the high-resolution X-ray crystal structures of homodimeric human GSTA1-1 in the apo form and in complex with S-hexyl glutathione (two data sets) are reported at 1.8, 1.5, and 1.3A respectively. At this level of resolution, distinct conformations of the alkyl chain of S-hexyl glutathione are observed, reflecting the nonspecific nature of the hydrophobic substrate binding site (H-site). Also, an extensive network of ordered water, including 75 discrete solvent molecules, traverses the open subunit-subunit interface and connects the glutathione binding sites in each subunit. In the highest-resolution structure, three glycerol moieties lie within this network and directly connect the amino termini of the glutathione molecules. A search for ligand binding sites with the docking program Molecular Operating Environment identified the ordered water network binding site, lined mainly with hydrophobic residues, suggesting an extended ligand binding surface for nonsubstrate ligands, the so-called ligandin site. Finally, detailed comparison of the structures reported here with previously published X-ray structures reveal a possible reaction coordinate for ligand-dependent conformational changes in the active site and the C-terminus.

Selected figure(s)

Figure 4.
Figure 4. Hydrogen bonding between S-hexyl GSH, protein side-chains, and glycerol molecules. Hydrogen bonds are depicted as thick bonds emphasizing how one glutathione is connected to the other across the dimer interface, which runs roughly vertically in this figure.

Figure 6.
Figure 6. Comparison of apo [apo, this work, (purple)], ethacrynic acid with no GSH [1GSF^5 (cyan)], S-ethacrynic acid GSH [1GSE^5 (red)], S-benzyl-GSH [1GUH^4 (yellow)], and S-hexyl GSH [GTX-GST-1.3, this work,(green)], in the region around GSH showing helix 9 and helix 4 as cylinders. Only selected side-chains are shown for clarity. The cofactors are drawn in ball-and-stick, while side-chains are shown as solid frames. Short connecting chains are shown in white. S-Hexyl GSH at the lower left can be seen to differ little among the structures. Arg15 at the lower left is hydrogen bonded to Glu104 on helix 4, which lies vertically at the right. Tyr9 is directly beneath GSH and Phe10 fans out underneath Phe220, which comes from helix 9, running horizontal at the top of the figure. Phe10 in the apo structure (purple) can be seen to occupy the place that Phe220 would occupy if the helix were localized in the apo structure. Phe222 is also seen to systematically correlate with the position of Phe10 (green/yellow/red/cyan: S-hexyl-GSH/S-benzyl GSH/ethacrynic acid GSH/no GSH). Arg216 also seems to correlate somewhat, although the order of the cyan and red side-chains are interchanged relative to the Phe222 order. Leu 213 is packed against Met 208 (also shown, just behind where the conjugates lie, near where the two cylinders appear to touch). Met 208 is also loosely in contact with Phe10 (there are no atoms directly between the two side-chains, although they are 4.5 Å apart and, in all except the present work, the thermal parameters for the SD and CE are high compared to its remaining side-chain atoms). Also shown on helix 4 are Leu107, Leu108, and Val111, residues that comprise part of the H site.

The above figures are reprinted by permission from John Wiley & Sons, Inc.: Proteins (2002, 48, 618-627) copyright 2002.

Figures were selected by the author.