Structural highlights
Publication Abstract from PubMedA Kunitz type dual inhibitor (TKI) of factor Xa (FXa) and trypsin was found in tamarind. It also shows prolongation of blood coagulation time. The deduced 185 amino acid sequence of TKI by cDNA cloning and sequence analysis revealed that it belongs to Kunitz type STI inhibitor family, however, has distorted Kunitz signature sequence due to insertion of Asn15 in the motif. TKI exhibited a competitive inhibitory activity against both factor Xa (K(i) of 220 nM) porcine and pancreatic trypsin (K(i) of 3.2 nM). The crystal structure of TKI shows beta-trefoil fold similar to Kunitz STI inhibitors, however, a distinct mobile reactive site, an inserted residue and loop beta7beta8 make it distinct from classical Kunitz inhibitors. The crystal structure of TKI-trypsin and 3D model of TKI-FXa complex revealed that distinct reactive site loop probably plays role in dual inhibition. The reactive site of TKI interacts with active site and two exosites (36-loop and autolysis loop) of FXa. Apart from Arg66 (P1), Arg64 (P3) is one of the most important residue responsible for the specificity of TKI towards FXa. Alongwith reactive site loop (beta4beta5), loop beta1 and beta7beta8 also interact with FXa and could further confer selectivity for FXa. We also presented the role of inserted Asn15 in stabilization of complexes. To the best of our knowledge, this is the first structure of FXa inhibitor belonging to Kunitz type inhibitor family and its unique structural and sequence features make TKI a novel potent inhibitor. (c) 2012 The Authors Journal compilation (c) 2012 FEBS. Structural basis for dual inhibitory role of tamarind Kunitz inhibitor (TKI) against factor Xa and trypsin.,Patil DN, Chaudhary A, Sharma AK, Tomar1 S, Kumar P FEBS J. 2012 Oct 25. doi: 10.1111/febs.12042. PMID:23094997[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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