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Structure paper

TitleStructure of the drug target ClpC1 unfoldase in action provides insights on antibiotic mechanism of action.
Journal, issue, pagesJ Biol Chem, Vol. 298, Issue 11, Page 102553, Year 2022
Publish dateOct 5, 2022
AuthorsKatharina Weinhäupl / Marcos Gragera / M Teresa Bueno-Carrasco / Rocío Arranz / Olga Krandor / Tatos Akopian / Raquel Soares / Eric Rubin / Jan Felix / Hugo Fraga /
PubMed AbstractThe 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 ...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.
External linksJ Biol Chem / PubMed:36208775 / PubMed Central
MethodsEM (single particle)
Resolution3.34 - 8.59 Å
Structure data

15240

8a8u

EMDB-15240, PDB-8a8u:
Mycobacterium tuberculosis ClpC1 hexamer structure
Method: EM (single particle) / Resolution: 3.62 Å

15241

8a8v

EMDB-15241, PDB-8a8v:
Mycobacterium tuberculosis ClpC1 hexamer structure bound to the natural product antibiotic Cyclomarin
Method: EM (single particle) / Resolution: 3.34 Å

15242

8a8w

EMDB-15242, PDB-8a8w:
Mycobacterium tuberculosis ClpC1 hexamer structure bound to the natural product antibiotic Ecumycin (class 1)
Method: EM (single particle) / Resolution: 4.29 Å

EMDB-15243: Mycobacterium tuberculosis ClpC1 hexamer structure bound to the natural product antibiotic ecumicin (class 2)
Method: EM (single particle) / Resolution: 8.59 Å

Chemicals

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

Source
  • mycobacterium tuberculosis (bacteria)
KeywordsCHAPERONE / hexamer / tuberculosis / drug target / protein quality control

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