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

• Published in: Acta crystallographica. Section F, Structural biology communications Structural biology communications, 2017-08, Vol.73 (8), p.469-475
• Main Authors: Torquato, Ricardo J. S., Lu, Stephen, Martins, Nadia Helena, Tanaka, Aparecida S., Pereira, Pedro José Barbosa
• Format: Article
• Language: English
• Subjects: Aedes - chemistry; Aedes - metabolism; Aedes aegypti; Amino Acid Sequence; Animals; anticoagulants; Aquatic insects; Binding Sites; Blood coagulation; Cloning, Molecular; Clotting; Crystal structure; Crystallography, X-Ray; Crystals; Dengue fever; Feeding; Fever; Gene Expression; Genetic Vectors - chemistry; Genetic Vectors - metabolism; High resolution; Insect Proteins - chemistry; Insect Proteins - genetics; Insect Proteins - metabolism; Insect Vectors - chemistry; Insect Vectors - metabolism; Kazal inhibitor; Molecular Docking Simulation; Mosquitoes; Pichia - genetics; Pichia - metabolism; Protease; Protease inhibitors; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Protein Multimerization; Proteinase; Proteinase inhibitors; protein–protein interactions; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Research Communications; salivary glands; Sequence Alignment; Sequence Homology, Amino Acid; Serine; Serine Peptidase Inhibitors, Kazal Type - chemistry; Serine Peptidase Inhibitors, Kazal Type - genetics; Serine Peptidase Inhibitors, Kazal Type - metabolism; Serine proteinase; Thrombin; Thrombin - antagonists & inhibitors; Thrombin - chemistry; Thrombin - genetics; Thrombin - metabolism; Trypsin; Vector-borne diseases; Viral diseases; Viruses; Yellow fever; Zika virus
• ISSN: 2053-230X; 2053-230X
• DOI: 10.1107/S2053230X17010007

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. Its haematophagic habits and urban habitat make the mosquito Aedes aegypti an important vector of a number of human viruses. Here, the high‐resolution crystal structure of AaTI, a noncanonical Kazal inhibitor from the saliva of A. aegypti, is presented, providing a molecular explanation for its inhibitory profile.