High-resolution structure of a Kazal-type serine protease inhibitor from the dengue vector Aedes aegypti

Abstract

Blood-feeding exoparasites are rich sources of protease inhibitors, and the mosquito Aedes aegypti, which is a vector of Dengue virus, Yellow fever virus, Chikungunya virus and Zika virus, is no exception. AaTI is a single-domain, noncanonical Kazal-type serine proteinase inhibitor from A. aegypti that recognizes both digestive trypsin-like serine proteinases and the central protease in blood clotting, thrombin, albeit with an affinity that is three orders of magnitude lower. Here, the 1.4 Å resolution crystal structure of AaTI is reported from extremely tightly packed crystals (∼22% solvent content), revealing the structural determinants for the observed inhibitory profile of this molecule.

Keywords: Aedes aegypti; Dengue fever; Kazal inhibitor; Yellow fever; Zika virus; anticoagulants; protein–protein interactions; salivary glands; thrombin; trypsin.