9BT6

Crystal structure of Chorismate Mutase from Mycobacterium tuberculosis in complex with the cyclic peptide inhibitor L2.1 (monoclinic P form)

9BT6 の概要

• エントリーDOI: 10.2210/pdb9bt6/pdb
• 分子名称: Secreted chorismate mutase, Peptide L2.1, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: chorismate mutase, mycobacterium tuberculosis, cyclic peptide inhibitor, isomerase
• 由来する生物種: Mycobacterium tuberculosis; 詳細
• タンパク質・核酸の鎖数: 16
• 化学式量合計: 200605.45

構造登録者

Liu, L.,Lovell, S.,Battaile, K.P.,Inglese, J. (登録日: 2024-05-14, 公開日: 2025-02-26, 最終更新日: 2025-03-26)

主引用文献

van Neer, R.H.P.,Dranchak, P.K.,Aitha, M.,Liu, L.,Carlson, E.K.,Jacobsen, I.E.,Battaile, K.,Fang, Y.,Tao, D.,Rai, G.,Padia, J.,Lovell, S.,Suga, H.,Inglese, J.
Active- and Allosteric-Site Cyclic Peptide Inhibitors of Secreted M. tuberculosis Chorismate Mutase.
Acs Infect Dis., 11:703-714, 2025

PubMed Abstract: The secreted Chorismate mutase enzyme of (*CM) is an underexplored potential target for the development of new antitubercular agents that are increasingly needed as antibiotic resistance rises in prevalence. As an enzyme suspected to be involved in virulence and host-pathogen interactions, disruption of its function could circumvent the difficulty of treating tuberculosis-infected granulomas. Drug development, however, is limited by novel ligand discovery. Currently, *CM activity is measured by using a low throughput acid/base-mediated product derivatization absorbance assay. Here, we utilized an RNA-display affinity selection approach enabled by the Random Peptides Integrated Discovery (RaPID) system to screen a vast library of macrocyclic peptides (MCP) for novel *CM ligands. Peptides identified from the RaPID selection, and analogs thereof identified by analyzing the selection population dynamics, produced a new class of *CM inhibiting MCPs. Among these were two noteworthy "chorismides", whose binding modes were elucidated by X-ray crystallography. Both were potent inhibitors of the CM enzyme activity. One was identified as an allosteric binding peptide revealing a novel inhibition approach, while the other is an active-site binding peptide that when conjugated to a fluorescent probe allowed for the development of a series of alternative fluorescence-based ligand-displacement assays that can be utilized for the assessment of potential *CM inhibitors.

PubMed: 39903128
DOI: 10.1021/acsinfecdis.4c00798

実験手法

X-RAY DIFFRACTION (2.8 Å)