3R6C

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

Summary for 3R6C

• Entry DOI: 10.2210/pdb3r6c/pdb
• Related: 3QQS 3QR9 3QS8 3QSA
• Descriptor: Anthranilate phosphoribosyltransferase, 1-O-pyrophosphono-5-O-phosphono-alpha-D-ribofuranose, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: anthranilate phosphoribosyltransferase, anthranilic acids, magnesium, tryptophan, structural genomics, tb structural genomics consortium, tbsgc, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 79425.68

Authors

Castell, A.,Short, F.L.,Lott, J.S.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2011-03-21, release date: 2012-09-26, Last modification date: 2024-02-21)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.83 Å)