Structure of BbKI, a disulfide-free plasma kallikrein inhibitor

Author(s)

Zhou, Dongwen ; Hansen, Daiane ; Shabalin, Ivan G. ; Gustchina, Alla ; Vieira, Debora F. ; de Brito, Marlon V. ; Araujo, Ana Paula U. ; Oliva, Maria Luiza V. ; Wlodawer, Alexander

• Document type: Journal article
• Source: ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS; v. 71, p. 8-pg., 2015-08-01.

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 angstrom 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. (AU)

• FAPESP's process: 09/53766-5 - Proteins from plant source with selectivity for inhibition of mammalian enzymes and their role as an anti-inflammatory, antithrombotic, anti-diabetic and anti-tumor agent
• Grantee: Maria Luiza Vilela Oliva
• Support Opportunities: Research Projects - Thematic Grants