1h4w

From Proteopedia

Revision as of 14:23, 5 November 2007

STRUCTURE OF HUMAN TRYPSIN IV (BRAIN TRYPSIN)

Overview

Severe neurodegradative brain diseases, like Alzheimer, are tightly linked, with proteolytic activity in the human brain. Proteinases expressed in the, brain, such as human trypsin IV, are likely to be involved in the, pathomechanism of these diseases. The observation of amyloid formed in the, brain of transgenic mice expressing human trypsin IV supports this, hypothesis. Human trypsin IV is also resistant towards all studied, naturally occurring polypeptide inhibitors. It has been postulated that, the substitution of Gly193 to arginine is responsible for this inhibitor, resistance. Here we report the X-ray structure of human trypsin IV in, complex with the inhibitor benzamidine at 1.7 A resolution. The overall, fold of human trypsin IV is similar to human trypsin I, with a root-mean, square deviation of only 0.5 A for all C(alpha) positions. The crystal, structure reveals the orientation of the side-chain of Arg193, which, occupies an extended conformation and fills the S2' subsite. An analysis, of surface electrostatic potentials shows an unusually strong clustering, of positive charges around the primary specificity pocket, to which the, side-chain of Arg193 also contributes. These unique features of the, crystal structure provide a structural basis for the enhanced inhibitor, resistance, and enhanced substrate restriction, of human trypsin IV.

About this Structure

1H4W is a Single protein structure of sequence from Homo sapiens with CA and BEN as ligands. Active as Trypsin, with EC number 3.4.21.4 Structure known Active Site: CAT. Full crystallographic information is available from OCA.

Reference

Crystal structure reveals basis for the inhibitor resistance of human brain trypsin., Katona G, Berglund GI, Hajdu J, Graf L, Szilagyi L, J Mol Biol. 2002 Feb 1;315(5):1209-18. PMID:11827488

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