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

Autores da FMUP
Participantes de fora da FMUP
- Weinhaupl, K
- Gragera, M
- Bueno Carrasco, MT
- Arranz, R
- Krandor, O
- Akopian, T
- Rubin, E
- Felix, J
- Fraga, H
Unidades de investigação
Abstract
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.
Dados da publicação
- ISSN/ISSNe:
- 0021-9258, 1083-351X
- Tipo:
- Article
- Páginas:
- -
- Link para outro recurso:
- www.scopus.com
Journal of Biological Chemistry Elsevier Inc.
Citações Recebidas na Scopus: 13
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Keywords
- Anti-Bacterial Agents; Bacterial Proteins; Humans; Molecular Chaperones; Mycobacterium tuberculosis; Tuberculosis; Electron microscopes; Medical imaging; Proteins; antiinfective agent; bacterial protein; chaperone; Bound-states; Chaperon; Cryo-electron microscopy; Drug development; Drug targets; Mechanism of action; Mycobacterium tuberculosis; N-terminal domains; Natural products; Protein degradation; amino terminal sequence; anion exchange chromatography; antibiotic therapy; Article; Bacillus subtilis; binding site; circular dichroism; computer model; conformational transition; cryoelectron microscopy; crystal structure; crystallography; DNA sequencing; enzyme activity; Escherichia coli; fluorometry; minimum inhibitory concentration; mitochondrial respiration; molecular docking; molecular dynamics; Mycobacterium tuberculosis; nonhuman; protein aggregation; protein conformation; protein degradation; protein interaction; protein structure; sequence homology; site directed mutagenesis; S
Campos de estudo
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Citar a publicação
Weinhaupl K,Gragera M,Bueno MT,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. 2022. 298. (11):102553. IF:4,800. (2).