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  • Title: Predicted three-dimensional structural models of venom serine protease inhibitors and their interactions with trypsin and chymotrypsin.
    Author: Azim MK, Grossmann JG, Zaidi ZH.
    Journal: J Nat Toxins; 1999 Oct; 8(3):363-84. PubMed ID: 10591040.
    Abstract:
    Three homology models of trypsin and chymotrypsin inhibitor polypeptides from snake venom of Naja naja naja and Leaf-nosed viper in the unbound state and in complex with trypsin and chymotrypsin were built based on homology to bovine pancreatic trypsin inhibitor (BPTI). These venom inhibitors belong to the Kunitz-type inhibitor family, which is characterized by a distinct tertiary fold with three-conserved disulfide bonds. The general folding pattern in these trypsin and chymotrypsin inhibitor homology models is conserved when compared to BPTI. The respective orientations of the inhibitors bound to trypsin/chymotrypsin are similar to that of BPTI bound to bovine trypsin/chymotrypsin. The principal binding loop structure of the inhibitors fills the active site of enzymes in a substrate-like conformation and forms a series of independent main-chain and side-chain interactions with enzymes. In order to provide the possible fingerprints for molecular recognition at the enzyme-inhibitor interface, a detailed theoretical analysis of the interactions between the principal binding loop of these inhibitors and active site of trypsin/chymotrypsin is performed based on available crystal structural, site-directed mutagenetic, kinetic, and sequence analysis studies. Despite the variations present at different positions of the principal binding loop of trypsin and chymotrypsin inhibitor models from Leaf-nosed viper and cobra Naja naja naja, respectively (designated as LnvTI and NCI), there are favorable subsite binding interactions which are expected to exhibit equally potent inhibitory activity as BPTI. On the contrary, significant mutations at several secondary specificity positions in the Naja naja naja trypsin inhibitor (designated as NTI) are likely to affect different inhibitor-enzyme-subsites interactions. This may explain the observed increased inhibitory activity of this polypeptide on a structural basis.
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