4AN7

Kunitz type trypsin inhibitor complex with porcine trypsin

Summary for 4AN7

• Entry DOI: 10.2210/pdb4an7/pdb
• Related: 1AKS 1AN1 1AVW 1AVX 1C9P 1D3O 1DF2 1EJA 1EPT 1EWU 1FMG 1FN6 1FNI 1H9H 1H9I 1LDT 1LT2 1MCT 1QQU 1S5S 1S6F 1S6H 1S81 1S82 1S83 1S84 1S85 1TFX 1TX6 1UHB 1V6D 1YF4 2A31 2A32 4AN6
• Descriptor: TRYPSIN, TRYPSIN INHIBITOR, CALCIUM ION, ... (4 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, kunitz, protease inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: SUS SCROFA (PIG); More
• Cellular location: Secreted, extracellular space: P00761
• Total number of polymer chains: 2
• Total formula weight: 45070.72

Authors

Patil, D.N.,Chaudhary, A.,Kumar, P. (deposition date: 2012-03-15, release date: 2012-11-07, Last modification date: 2024-11-20)

Primary citation

Patil, D.N.,Chaudhary, A.,Sharma, A.K.,Tomar, S.,Kumar, P.
Structural Basis for Dual Inhibitory Role of Tamarind Kunitz Inhibitor (Tki) Against Factor Xa and Trypsin.
FEBS J., 279:4547-, 2012

PubMed Abstract: A 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 the Kunitz type soybean trypsin inhibitor (STI) family; however, it has a distorted Kunitz signature sequence due to insertion of Asn15 in the motif. TKI exhibited a competitive inhibitory activity against both FXa (K(i)  = 220 nm) and porcine pancreatic trypsin (K(i)  = 3.2 nm). The crystal structure of TKI shows a β-trefoil fold similar to Kunitz STI inhibitors; however, a distinct mobile reactive site, an inserted residue and loop β7β8 make it distinct from classical Kunitz inhibitors. The crystal structure of TKI-trypsin and a 3D model of TKI-FXa complex revealed that the distinct reactive site loop probably plays a role in dual inhibition. The reactive site of TKI interacts with an active site and two exosites (36 loop and autolysis loop) of FXa. Apart from Arg66 (P1), Arg64 (P3) is one of the most important residues responsible for the specificity of TKI towards FXa. Along with the reactive site loop (β4β5), loops β1 and β7β8 also interact with FXa and could further confer selectivity for FXa. We also present the role of inserted Asn15 in the stabilization of complexes. To the best of our knowledge, this is the first structure of FXa inhibitor belonging to the Kunitz type inhibitor family and its unique structural and sequence features make TKI a novel potent inhibitor.

PubMed: 23094997
DOI: 10.1111/FEBS.12042

Experimental method

X-RAY DIFFRACTION (2.23 Å)