PDBsum entry 2zjf

Hydrolase

PDB id: 2zjf

Contents

Protein chain

346 a.a. *

Ligands

ACT ×3

BSU

Waters ×120

* Residue conservation analysis

PDB id:

2zjf

Name:

Hydrolase

Title:

Crystal structure of mycobacterium tuberculosis epoxide hydrolase b complexed with an inhibitor

Structure:

Probable epoxide hydrolase ephb. Chain: a. Synonym: epoxide hydratase, epoxide hydrolase. Engineered: yes

Source:

Mycobacterium tuberculosis. Organism_taxid: 83332. Strain: h37rv. Atcc: 25618. Gene: ephb, mt1988, rv1938. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.

Resolution:

2.40Å R-factor: 0.202 R-free: 0.256

Authors:

B.K.Biswal,Tb Structural Genomics Consortium (Tbsgc)

Key ref:

B.K.Biswal et al. (2008). The molecular structure of epoxide hydrolase B from Mycobacterium tuberculosis and its complex with a urea-based inhibitor. J Mol Biol, 381, 897-912. PubMed id: 18585390 DOI: 10.1016/j.jmb.2008.06.030

Date:

07-Mar-08 Release date: 01-Apr-08

Protein chain

P95276  (EPHB_MYCTO) -  Epoxide hydrolase B from Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh)

Seq: 356 a.a.

Struc: 346 a.a.

Enzyme reactions

• Enzyme class: E.C.3.3.2.10 - soluble epoxide hydrolase.
• Reaction: an epoxide + H2O = an ethanediol

epoxide (Bound ligand (Het Group name = ACT) matches with 50.00% similarity) + H2O = ethanediol

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

Key reference

DOI no: 10.1016/j.jmb.2008.06.030

J Mol Biol 381:897-912 (2008)

PubMed id: 18585390

The molecular structure of epoxide hydrolase B from Mycobacterium tuberculosis and its complex with a urea-based inhibitor.

B.K.Biswal, C.Morisseau, G.Garen, M.M.Cherney, C.Garen, C.Niu, B.D.Hammock, M.N.James.

ABSTRACT

Mycobacterium tuberculosis (Mtb), the intracellular pathogen that infects macrophages primarily, is the causative agent of the infectious disease tuberculosis in humans. The Mtb genome encodes at least six epoxide hydrolases (EHs A to F). EHs convert epoxides to trans-dihydrodiols and have roles in drug metabolism as well as in the processing of signaling molecules. Herein, we report the crystal structures of unbound Mtb EHB and Mtb EHB bound to a potent, low-nanomolar (IC(50) approximately 19 nM) urea-based inhibitor at 2.1 and 2.4 A resolution, respectively. The enzyme is a homodimer; each monomer adopts the classical alpha/beta hydrolase fold that composes the catalytic domain; there is a cap domain that regulates access to the active site. The catalytic triad, comprising Asp104, His333 and Asp302, protrudes from the catalytic domain into the substrate binding cavity between the two domains. The urea portion of the inhibitor is bound in the catalytic cavity, mimicking, in part, the substrate binding; the two urea nitrogen atoms donate hydrogen bonds to the nucleophilic carboxylate of Asp104, and the carbonyl oxygen of the urea moiety receives hydrogen bonds from the phenolic oxygen atoms of Tyr164 and Tyr272. The phenolic oxygen groups of these two residues provide electrophilic assistance during the epoxide hydrolytic cleavage. Upon inhibitor binding, the binding-site residues undergo subtle structural rearrangement. In particular, the side chain of Ile137 exhibits a rotation of around 120 degrees about its C(alpha)-C(beta) bond in order to accommodate the inhibitor. These findings have not only shed light on the enzyme mechanism but also have opened a path for the development of potent inhibitors with good pharmacokinetic profiles against all Mtb EHs of the alpha/beta type.

Selected figure(s)

Figure 2.
Fig. 2. (a) A surface charge distribution representation of Mtb EHB. The red regions of the surface correspond to negative charges; the blue corresponds to positively charged region and the white regions correspond to neutral charges, respectively. (b) Rotation of the Mtb EHB around a vertical axis by 180° as indicated.

Figure 8.
Fig. 8. A schematic picture showing the reaction mechanism of how Mtb EHB hydrolyses the epoxide substrate. The reaction proceeds by the nucleophilic attack by Asp104.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2008, 381, 897-912) copyright 2008.

Figures were selected by an automated process.