Download MendeleyThe X-ray structure of carboxypeptidase A inhibited by a thiirane mechanism-based inhibitor
Fernandez, D., Testero, S., Vendrell, J., Aviles, F.X., Mobashery, S.(2010) Chem Biol Drug Des 75: 29-34
- PubMed: 19895506
- DOI: https://doi.org/10.1111/j.1747-0285.2009.00907.x
- Primary Citation of Related Structures:
3I1U - PubMed Abstract:
The three-dimensional X-ray crystal structure of carboxypeptidase A, a zinc-dependent hydrolase, covalently modified by a mechanism-based thiirane inactivator, 2-benzyl-3,4-epithiobutanoic acid, has been solved to 1.38 A resolution. The interaction of the thiirane moiety of the inhibitor with the active site zinc ion promotes its covalent modification of Glu-270 with the attendant opening of the thiirane ring. The crystal structure determination at high resolution allowed for the clear visualization of the covalent ester bond to the glutamate side chain. The newly generated thiol from the inhibitor binds to the catalytic zinc ion in a monodentate manner, inducing a change in the zinc ion geometry and coordination, while its benzyl group fits into the S1' specificity pocket of the enzyme. The inhibitor molecule is distorted at the position of the carbon atom that is involved in the ester bond linkage on one side and the zinc coordination on the other. This particular type of thiirane-based metalloprotease inhibitor is for the first time analyzed in complex to the target protease at high resolution and may be used as a general model for zinc-dependent proteases.
Organizational Affiliation:
Departament de Bioquímica i Biologia Molecular, Facultat de Biociències, and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
