Structural Findings and Molecular Modeling Approach of a TFPI-Like Inhibitor

Author(s)

Mesquita Pasqualoto, Kerly Fernanda ^[1] ; Balan, Andrea ^[2] ; Barreto, Sandra Alves ^[1] ; Simons, Simone Michaela ^[1] ; Chudzinski-Tavassi, Ana Marisa ^[1]

Affiliation

^[1] Inst Butantan, Lab Bioquim & Biofis, BR-05503900 Sao Paulo - Brazil

^[2] Brazilian Natl Lab Biosci, Ctr Struct & Mol Biol, BR-13084971 Campinas, SP - Brazil

• Document type: Journal article
• Source: PROTEIN AND PEPTIDE LETTERS; v. 21, n. 5, p. 452-457, MAY 2014.
• Web of Science Citations: 6

Abstract

Specific blood coagulation inhibitors from hematophagous organisms, with different structures and novel mechanism of action, have been described and they represent promising agents for the treatment of a variety of human diseases related to coagulation and cancer. In our lab, the salivary glands transcriptome of the adult Amblyomma cajennense tick was previously characterized by expressed sequence tags (EST). A transcript that codes for a tissue factor pathway inhibitor (TFPI)-like protein with unique structure was found, and the recombinant form of this protein was named Amblyomin-X. This protein was able to inhibit the factor Xa amidolytic activity and the activation of factor X by the extrinsic tenase complex (FVIIa/TF). Herein, it was performed functional and structural evaluation of Amblyomin-X. The CD assay and molecular dynamics simulations revealed that Amblyomin-X is structurally stable and the naturally unfolded regions as well as the presence of three disulfide bridges in its Kunitz-type domain seem to sustain its inhibitory activity. Regarding the electrostatic potential mapping on the Kunitz-type region, the pattern of charged residues was not quite the same in comparison to human TFPI-1 and TFPI-2, pointing out there might be distinct functional and structural features, which are going to be experimentally exploited. (AU)