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

• Tipo: Artigo em Revista Científica Internacional
• Data: 2022

Autores

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

Revista

Título: Journal of Biological Chemistry

Vol. 298

ISSN: 0021-9258

Editora: Elsevier

Indexação

ISI Web of Knowledge - 2 Citações

Scopus

Outras Informações

ID Authenticus: 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 11