11OP

Crystal Structure of M. tuberculosis ClpP1P2 bound to ONC201

This is a non-PDB format compatible entry.

Summary for 11OP

• Entry DOI: 10.2210/pdb11op/pdb
• Descriptor: ATP-dependent Clp protease proteolytic subunit 2, TRIETHYLENE GLYCOL, 2-(2-METHOXYETHOXY)ETHANOL, ... (12 entities in total)
• Functional Keywords: peptidase, protease, mycobacteria, antibiotic, tuberculosis, acyldepsipeptide, proteostasis
• Biological source: Mycobacterium tuberculosis H37Rv; More
• Total number of polymer chains: 14
• Total formula weight: 322626.12

Authors

Burnside, C.M.,Fei, F.,Schmitz, K.R.,Sello, J.K. (deposition date: 2026-03-06, release date: 2026-09-23)

Primary citation

Fei, F.,Burnside, C.M.,Lun, S.,Wee, D.,Kaur, M.,Anderson, H.R.,McCarroll, M.N.,Richardson, A.E.,Neglia, S.,Liu, H.M.,Wang, X.,Gupta, S.,Rhee, K.Y.,Wright, G.D.,Bryson, B.D.,Oehlers, S.H.,Bishai, W.R.,Schmitz, K.R.,Sello, J.K.
Structural and Mechanistic Studies of ADEPs Yield Potent Antibacterials and a Drug Formulation Strategy for Tuberculosis.
J.Med.Chem., 2026

PubMed Abstract: Acyldepsipeptides (ADEPs) are potent ClpP dysregulators that are active against a range of Gram-positive bacteria, but have limited potency against Mycobacterium tuberculosis (Mtb). To address potency, we employed a strategy of macrocycle rigidification and side-chain optimization enabled by a novel solid-phase peptide synthesis route. Among 35 compounds synthesized, ADEP 19 was as much as 12-fold more potent against Mtb and other bacteria than ADEP 4, the prototypical ADEP having efficacy in animal infection models. Biophysical, enzymatic, crystallographic, and microbiological studies showed that conformational restriction of both the macrocycle and side chain enhanced ClpP1P2 binding affinity and antibacterial potency. Our observation that ADEP 19 caused a reduction in intracellular ATP in Mtb suggested potential synergy of ADEPs with bedaquiline (BDQ), a tuberculosis drug that inhibits ATP synthesis. Checkerboard assays and experiments in a zebrafish TB model affirmed synergy between ADEP 19 and BDQ that could be leveraged to address BDQ-associated cardiotoxicity.

PubMed: 42727081
DOI: 10.1021/acs.jmedchem.6c00893

Experimental method

X-RAY DIFFRACTION (3.11 Å)