9BT7
Crystal structure of Chorismate Mutase from Mycobacterium tuberculosis in complex with the cyclic peptide inhibitor D1.3
Summary for 9BT7
| Entry DOI | 10.2210/pdb9bt7/pdb |
| Descriptor | Secreted chorismate mutase, Cyclic peptide inhibitor D1.3 (3 entities in total) |
| Functional Keywords | chorismate mutase, mycobacterium tuberculosis, cyclic peptide inhibitor, isomerase |
| Biological source | Mycobacterium tuberculosis More |
| Total number of polymer chains | 4 |
| Total formula weight | 49718.99 |
| Authors | Liu, L.,Lovell, S.,Battaile, K.P.,Inglese, J. (deposition date: 2024-05-14, release date: 2025-02-26, Last modification date: 2025-03-26) |
| Primary citation | 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 Cited by 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: 39903128DOI: 10.1021/acsinfecdis.4c00798 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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