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Acta Crystallogr F Struct Biol Commun. 2015 Aug;71(Pt 8):1055-62. doi: 10.1107/S2053230X15011127. Epub 2015 Jul 29.

Structure of BbKI, a disulfide-free plasma kallikrein inhibitor.

Author information

1
Macromolecular Crystallography Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
2
Universidade Federal de São Paulo-Escola Paulista de Medicina, Rua Três de Maio 100, 04044-020 São Paulo-SP, Brazil.
3
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
4
Institute of Physics of São Carlos, University of São Paulo, Avenida Trabalhador Sãocarlense 400, 13560-970 São Carlos-SP, Brazil.

Abstract

A serine protease inhibitor from Bauhinia bauhinioides (BbKI) belongs to the Kunitz family of plant inhibitors, which are common in plant seeds. BbKI does not contain any disulfides, unlike most other members of this family. It is a potent inhibitor of plasma kallikrein, in addition to other serine proteases, and thus exhibits antithrombotic activity. A high-resolution crystal structure of recombinantly expressed BbKI was determined (at 1.4 Å resolution) and was compared with the structures of other members of the family. Modeling of a complex of BbKI with plasma kallikrein indicates that changes in the local structure of the reactive loop that includes the specificity-determining Arg64 are necessary in order to explain the tight binding. An R64A mutant of BbKI was found to be a weaker inhibitor of plasma kallikrein, but was much more potent against plasmin, suggesting that this mutant may be useful for preventing the breakup of fibrin and maintaining clot stability, thus preventing excessive bleeding.

KEYWORDS:

Kunitz inhibitor; crystal structure; kallikrein; β-trefoil

PMID:
26249699
PMCID:
PMC4528941
DOI:
10.1107/S2053230X15011127
[Indexed for MEDLINE]
Free PMC Article

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