8A8U

Mycobacterium tuberculosis ClpC1 hexamer structure

Summary for 8A8U

• Entry DOI: 10.2210/pdb8a8u/pdb
• Related: 8A8U 8A8V 8A8W
• EMDB information: 15240 15241 15242 15243
• Descriptor: ATP-dependent Clp protease ATP-binding subunit ClpC1, Bound polypeptide, ADENOSINE-5'-DIPHOSPHATE (3 entities in total)
• Functional Keywords: hexamer, tuberculosis, drug target, protein quality control, chaperone
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 7
• Total formula weight: 574799.61

Authors

Felix, J.,Fraga, H.,Gragera, M.,Bueno, T.,Weinhaeupl, K. (deposition date: 2022-06-24, release date: 2022-10-26, Last modification date: 2024-07-24)

Primary citation

Weinhaupl, K.,Gragera, M.,Bueno-Carrasco, M.T.,Arranz, R.,Krandor, O.,Akopian, T.,Soares, R.,Rubin, E.,Felix, J.,Fraga, H.
Structure of the drug target ClpC1 unfoldase in action provides insights on antibiotic mechanism of action.
J.Biol.Chem., 298:102553-102553, 2022

PubMed Abstract: The unfoldase ClpC1 is one of the most exciting drug targets against tuberculosis. This AAA+ unfoldase works in cooperation with the ClpP1P2 protease and is the target of at least four natural product antibiotics: cyclomarin, ecumicin, lassomycin, and rufomycin. Although these molecules are promising starting points for drug development, their mechanisms of action remain largely unknown. Taking advantage of a middle domain mutant, we determined the first structure of Mycobacterium tuberculosis ClpC1 in its apo, cyclomarin-, and ecumicin-bound states via cryo-EM. The obtained structure displays features observed in other members of the AAA+ family and provides a map for further drug development. While the apo and cyclomarin-bound structures are indistinguishable and have N-terminal domains that are invisible in their respective EM maps, around half of the ecumicin-bound ClpC1 particles display three of their six N-terminal domains in an extended conformation. Our structural observations suggest a mechanism where ecumicin functions by mimicking substrate binding, leading to ATPase activation and changes in protein degradation profile.

PubMed: 36208775
DOI: 10.1016/j.jbc.2022.102553

Experimental method

ELECTRON MICROSCOPY (3.62 Å)