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. 1994 Apr 1;13(7):1502–1507. doi: 10.1002/j.1460-2075.1994.tb06411.x

Macromolecular chelation as an improved mechanism of protease inhibition: structure of the ecotin-trypsin complex.

M E McGrath 1, T Erpel 1, C Bystroff 1, R J Fletterick 1
PMCID: PMC394978  PMID: 8156987

Abstract

The 2.4 A crystal structure (R = 0.180) of the serine protease inhibitor ecotin was determined in a complex with trypsin. Ecotin's dimer structure provides a second discrete and distal binding site for trypsin and, as shown by modelling experiments, other serine proteases. The second site is approximately 45 A from the reactive/active site of the complex and features 13 hydrogen bonds, including six that involve carbonyl oxygen atoms and four bridged by water molecules. Contacts ecotin makes with trypsin's active site are similar to, though more extensive than, those found between trypsin and basic pancreatic trypsin inhibitor. The side chain of ecotin Met84 is found in the substrate binding pocket of trypsin where it makes few contacts, but also does not disrupt the solvent structure or cause misalignment of the scissile bond. This first case of protein dimerization being used to augment binding energy and allow chelation of a target protein provides a new model for protein-protein interactions and for protease inhibition.

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