3twp

Crystal structure of M. tuberculosis TrpD in complex with an inhibitor

spinqualitylabelsall models 3twp, resolution 1.83Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3twp is a 4 chain structure with sequence from "bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL, MG, PRP, SAL Related: 3qr9, 3qqs, 3qs8, 3r6c, 3qsa, 3r88 Gene: MT2248, MTCY190.03c, Rv2192c, trpD ("Bacillus tuberculosis" (Zopf 1883) Klein 1884) Activity: Anthranilate phosphoribosyltransferase, with EC number 2.4.2.18 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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 (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 non-catalytic anthranilate binding site, previously hypothesized to have a role in substrate capture. The potencies of the inhibitors were measured, yielding Ki values from 1.5 - 119 muM, with the strongest inhibition displayed by a bi-anthranilate 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 anti-tuberculosis drugs with a novel mode of action. Substrate capture mechanism of Mycobacterium tuberculosis anthranilate phosphoribosyltransferase provides a mode for inhibition.,Castell A, Short FL, Evans GL, Cookson TV, Bulloch EM, Joseph DD, Lee CE, Parker EJ, Baker EN, Lott JS Biochemistry. 2013 Jan 30. PMID:23363292 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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