9DIN

Structure of ClpC1 N-terminal Domain complexed with semi-synthetic Rufomycin analog

This is a non-PDB format compatible entry.

Summary for 9DIN

• Entry DOI: 10.2210/pdb9din/pdb
• Related PRD ID: PRD_002569
• Descriptor: ATP-dependent Clp protease ATP-binding subunit ClpC1, Rufomycin analog, ACETIC ACID, ... (6 entities in total)
• Functional Keywords: clpc1 atpase, rufomycin, antibiotic, clpc1-ntd-complex, chaperone, chaperone-antibiotic complex, chaperone/antibiotic
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 2
• Total formula weight: 18813.45

Authors

Abad-Zapatero, C.,Wolf, N.M. (deposition date: 2024-09-05, release date: 2025-04-16, Last modification date: 2025-05-07)

Primary citation

Zhou, B.,Shetye, G.,Klein, L.L.,Wolf, N.M.,Lee, H.,McAlpine, J.B.,Harris, G.,Chen, S.N.,Suh, J.W.,Cho, S.H.,Franzblau, S.G.,Abad-Zapatero, C.,Pauli, G.F.
Structure-Based Analysis of Semisynthetic Anti-TB Rufomycin Analogues.
J.Nat.Prod., 88:907-925, 2025

PubMed Abstract: This study employed structural information from cocrystals of rufomycin 4 () and caseinolytic protein C1 (ClpC1)-NTD-wt to guide design and semisynthesis of rufomycin analogues, evaluate their antituberculosis (TB) biological profiles, and establish structure-activity relationships (SAR). Covering three regions of interest (ROIs, A-C) as modification sites, 14 of the 30 semisynthetic analogues (-) showed similar or improved MICs relative to the main natural precursors, rufomycins 4/6 (). Compounds and exhibited up to 10-fold enhanced potency against () in vitro, with MIC values of 1.9 and 1.4 nM, respectively. Evaluation of ClpC1-binding properties used existing ClpC1-NTD complexes with rufomycin 4 (PDB: 6cn8) and ecumicin (PDB: 6pbs) as references. The newly reported X-ray ClpC1-NTD cocrystal structure of (syn. But4-Cl) revealed significant conformational effects involving the side chains of certain amino acids of the heptapeptide and confirmed the importance of ROIs A-C for medicinal chemistry efforts. Observed interactions of the -terminal tail of ClpC1 with the rufomycin analogues vs ecumicin explains their different modes of inactivating the ClpC1/P1/P2 homeostatic machinery. Collectively, the observations inform further SAR optimization strategies for the rufomycin class of antibiotics and complement our understanding of their mode of action.

PubMed: 40126472
DOI: 10.1021/acs.jnatprod.4c01266

Experimental method

X-RAY DIFFRACTION (1.64 Å)