9BBJ
M. tuberculosis ClpC1-NTD complexed with a click chemistry analog of Rufomycin
This is a non-PDB format compatible entry.
Summary for 9BBJ
| Entry DOI | 10.2210/pdb9bbj/pdb |
| Related | 6cn8 6pbs |
| Descriptor | ATP-dependent Clp protease ATP-binding subunit ClpC1, Click chemistry analog of Rufomycin (2 entities in total) |
| Functional Keywords | m. tuberculosis, clpc1, rufomycin, click-chemistry, antibiotic |
| Biological source | Mycobacterium tuberculosis More |
| Total number of polymer chains | 2 |
| Total formula weight | 18493.34 |
| Authors | Abad-Zapatero, C.,Ratia, K. (deposition date: 2024-04-05, release date: 2025-12-10, Last modification date: 2026-01-07) |
| Primary citation | Ratia, K.,Jin, S.,Abad-Zapatero, C.,Shetye, G.S.,Demissie, R.,Qader, M.,Beautrait, A.,Nikolic, D.S.,Wolf, N.M.,Rubin, E.J.,Krandor, O.,Serbina, N.,Li, G.,Pauli, G.F.,Klein, L.L.,Cho, S.,Franzblau, S.G.,Fotouhi, N.,Kaneko, T.,Lee, H. Unique Interactions of Novel Rufomycin "Click Chemistry" Analogs with Mtb ClpC1 and Implications. J.Med.Chem., 68:26298-26310, 2025 Cited by PubMed Abstract: Disrupting protein homeostasis in () by targeting the ClpC1P1P2 proteolytic complex is a promising anti-TB strategy. We synthesized conformationally constrained monomeric and dimeric rufomycin 4/6 (RUF) analogs via click chemistry. While most monomeric analogs were inactive, dimeric analogs displayed potent anti- activity. Surface plasmon resonance revealed tight, slow-dissociating binding of dimers to the ClpC1 N-terminal domain (ClpC1), indicating prolonged residency time. X-ray crystallography and size exclusion chromatography demonstrated that dimeric analogs induce NTD dimerization, likely shifting the equilibrium toward enzymatically active hexamers rather than inactive decamers. Dimers enhanced ATPase activity over 10-fold, surpassing that of ecumicin (8-fold) and far exceeding RUF (<2-fold). Notably, our dimers bind two NTDs per molecule (1:2), contrasting with RUF (1:1) and ecumicin (2:1), suggesting a distinct activation mechanism. These RUF-based click chemistry dimers represent potent ClpC1 modulators with extended residency and novel stoichiometry, offering promising tools for studying protein degradation. PubMed: 41384615DOI: 10.1021/acs.jmedchem.5c02416 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.56 Å) |
Structure validation
Download full validation report
