1shl

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spinqualitylabelsall models 1shl, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CASPASE-7 IN COMPLEX WITH FICA ALLOSTERIC INHIBITOR

Overview

Allosteric regulation of proteins by conformational change is a primary, means of biological control. Traditionally it has been difficult to, identify and characterize novel allosteric sites and ligands that freeze, these conformational states. We present a site-directed approach using, Tethering for trapping inhibitory small molecules at sites away from the, active site by reversible disulfide bond formation. We screened a library, of 10,000 thiol-containing compounds against accessible cysteines of two, members of the caspase family of proteases, caspase-3 and -7. We, discovered a previously unreported and conserved allosteric site in a deep, cavity at the dimer interface 14 A from the active site. This site, contains a natural cysteine that, when disulfide-bonded with either of two, specific compounds, inactivates these proteases. The allosteric site is, functionally coupled to the active site, such that binding of the, compounds at the allosteric site prevents peptide binding at the active, site. The x-ray crystal structures of caspase-7 bound by either compound, demonstrates that they inhibit caspase-7 by trapping a zymogen-like, conformation. This approach may be useful to identify new allosteric sites, from natural or engineered cysteines, to study allosteric transitions in, proteins, and to nucleate drug discovery efforts.

About this Structure

1SHL is a Single protein structure of sequence from Homo sapiens with FXN as ligand. Full crystallographic information is available from OCA.

Reference

Discovery of an allosteric site in the caspases., Hardy JA, Lam J, Nguyen JT, O'Brien T, Wells JA, Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12461-6. Epub 2004 Aug 16. PMID:15314233

Page seeded by OCA on Mon Nov 12 19:13:47 2007