PDBsum entry 3r6c

Transferase/transferase inhibitor

PDB id: 3r6c

Contents

Protein chains

346 a.a.

Ligands

PRP ×2

17N ×3

GOL

Metals

_MG ×4

Waters ×572

PDB id:

3r6c

Name:

Transferase/transferase inhibitor

Title:

Anthranilate phosphoribosyltransferase (trpd) from mycobacterium tuberculosis (complex with inhibitor acs179)

Structure:

Anthranilate phosphoribosyltransferase. Chain: a, b. Engineered: yes

Source:

Mycobacterium tuberculosis. Organism_taxid: 1773. Gene: mt2248, mtcy190.03c, trpd. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.83Å R-factor: 0.188 R-free: 0.227

Authors:

A.Castell,F.L.Short,J.S.Lott,Tb Structural Genomics Consortium (Tbsgc)

Key ref:

A.Castell et al. (2013). The substrate capture mechanism of Mycobacterium tuberculosis anthranilate phosphoribosyltransferase provides a mode for inhibition. Biochemistry, 52, 1776-1787. PubMed id: 23363292 DOI: 10.1021/bi301387m

Date:

21-Mar-11 Release date: 26-Sep-12

Protein chains

P9WFX5  (TRPD_MYCTU) -  Anthranilate phosphoribosyltransferase from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)

Seq: 370 a.a.

Struc: 346 a.a.

Enzyme reactions

• Enzyme class: E.C.2.4.2.18 - anthranilate phosphoribosyltransferase.
• Pathway: Tryptophan Biosynthesis
• Reaction: N-(5-phospho-beta-D-ribosyl)anthranilate + diphosphate = 5-phospho-alpha- D-ribose 1-diphosphate + anthranilate

N-(5-phospho-beta-D-ribosyl)anthranilate (Bound ligand (Het Group name = PRP) matches with 40.91% similarity) + diphosphate = 5-phospho-alpha- D-ribose 1-diphosphate + anthranilate

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

reference

DOI no: 10.1021/bi301387m

Biochemistry 52:1776-1787 (2013)

PubMed id: 23363292

The substrate capture mechanism of Mycobacterium tuberculosis anthranilate phosphoribosyltransferase provides a mode for inhibition.

A.Castell, F.L.Short, G.L.Evans, T.V.Cookson, E.M.Bulloch, D.D.Joseph, C.E.Lee, E.J.Parker, E.N.Baker, J.S.Lott.

ABSTRACT

Anthranilate phosphoribosyltransferase (AnPRT, EC 2.4.2.18) is a homodimeric enzyme that catalyzes the reaction between 5'-phosphoribosyl 1'-pyrophosphate (PRPP) and anthranilate, as part of the tryptophan biosynthesis pathway. Here we present the results of the first chemical screen for inhibitors against Mycobacterium tuberculosis AnPRT (Mtb-AnPRT), along with crystal structures of Mtb-AnPRT in complex with PRPP and several inhibitors. Previous work revealed that PRPP is bound at the base of a deep cleft in Mtb-AnPRT and predicted two anthranilate binding sites along the tunnel leading to the PRPP binding site. Unexpectedly, the inhibitors presented here almost exclusively bound at the entrance of the tunnel, in the presumed noncatalytic anthranilate binding site, previously hypothesized to have a role in substrate capture. The potencies of the inhibitors were measured, yielding Ki values of 1.5-119 μM, with the strongest inhibition displayed by a bianthranilate compound that makes hydrogen bond and salt bridge contacts with Mtb-AnPRT via its carboxyl groups. Our results reveal how the substrate capture mechanism of AnPRT can be exploited to inhibit the enzyme's activity and provide a scaffold for the design of improved Mtb-AnPRT inhibitors that may ultimately form the basis of new antituberculosis drugs with a novel mode of action.