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TitleStructural analysis of Mycobacterium tuberculosis M13 metalloprotease Zmp1 open states.
Journal, issue, pagesStructure, Vol. 29, Issue 7, Page 709-720.e3, Year 2021
Publish dateJul 1, 2021
AuthorsWenguang G Liang / Jordan M Mancl / Minglei Zhao / Wei-Jen Tang /
PubMed AbstractZinc metalloprotease 1 (Zmp1), a Mycobacterium tuberculosis 75 kDa secreted enzyme, mediates key stages of tuberculosis disease progression. The biological activity of Zmp1 presumably stems from its ...Zinc metalloprotease 1 (Zmp1), a Mycobacterium tuberculosis 75 kDa secreted enzyme, mediates key stages of tuberculosis disease progression. The biological activity of Zmp1 presumably stems from its ability to degrade bacterium- and/or host-derived peptides. The crystal structures of Zmp1 and related M13 metalloproteases, such as neprilysin and endothelin-converting enzyme-1 were determined only in the closed conformation, which cannot capture substrates or release proteolytic products. Thus, the mechanisms of substrate binding and selectivity remain elusive. Here we report two open-state cryo-EM structures of Zmp1, revealed by our SAXS analysis to be the dominant states in solution. Our structural analyses reveal how ligand binding induces a conformational switch in four linker regions to drive the rigid body motion of the D1 and D2 domains, which form the sizable catalytic chamber. Furthermore, they offer insights into the catalytic cycle and mechanism of substrate recognition of M13 metalloproteases for future therapeutic innovations.
External linksStructure / PubMed:33378640 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 4.6 Å
Structure data

22252

6xly

EMDB-22252, PDB-6xly:
CRYOEM STRUCTURE OF MYCOBACTERIUM TUBERCULOSIS ZINC METALLOPROTEASE ZMP1 IN OPEN STATE
Method: EM (single particle) / Resolution: 3.1 Å

22630

7k1v

EMDB-22630, PDB-7k1v:
Partial open state of Mycobacterium tuberculosis zinc metalloprotease 1
Method: EM (single particle) / Resolution: 4.6 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • mycobacterium tuberculosis (strain atcc 25618 / h37rv) (bacteria)
KeywordsHYDROLASE / Open state

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