Structure of the drug target ClpC1 unfoldase in action provides insights on antibiotic mechanism of action

• Type: Article in International Scientific Journal
• Date: 2022

Authors

Weinhaupl, K (Author) Other; Gragera, M (Author) Other; Bueno Carrasco, MT (Author) Other; Arranz, R (Author) Other; Krandor, O (Author) Other; Akopian, T (Author) Other; soares, r (Author) FMUP; Rubin, E (Author) Other; Felix, J (Author) Other; Fraga, H (Author) Other

Journal

Title: Journal of Biological Chemistry

Vol. 298

ISSN: 0021-9258

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 2 Citations

Scopus

Other information

Authenticus ID: P-00X-GNG

DOI: 10.1016/j.jbc.2022.102553

Abstract (EN): The unfoldase ClpC1 is one of the most exciting drug targets against tuberculosis. This AAA+ unfoldase works in coopera-tion 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 Myco-bacterium 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11