3R6C

Anthranilate phosphoribosyltransferase (trpD) from Mycobacterium tuberculosis (complex with inhibitor ACS179)

3R6C の概要

• エントリーDOI: 10.2210/pdb3r6c/pdb
• 関連するPDBエントリー: 3QQS 3QR9 3QS8 3QSA
• 分子名称: Anthranilate phosphoribosyltransferase, 1-O-pyrophosphono-5-O-phosphono-alpha-D-ribofuranose, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: anthranilate phosphoribosyltransferase, anthranilic acids, magnesium, tryptophan, structural genomics, tb structural genomics consortium, tbsgc, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79425.68

構造登録者

Castell, A.,Short, F.L.,Lott, J.S.,TB Structural Genomics Consortium (TBSGC) (登録日: 2011-03-21, 公開日: 2012-09-26, 最終更新日: 2024-02-21)

主引用文献

Castell, A.,Short, F.L.,Evans, G.L.,Cookson, T.V.,Bulloch, E.M.,Joseph, D.D.,Lee, C.E.,Parker, E.J.,Baker, E.N.,Lott, J.S.
The Substrate Capture Mechanism of Mycobacterium tuberculosis Anthranilate Phosphoribosyltransferase Provides a Mode for Inhibition.
Biochemistry, 52:1776-1787, 2013

PubMed 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.

PubMed: 23363292
DOI: 10.1021/bi301387m

実験手法

X-RAY DIFFRACTION (1.83 Å)