2nqg

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spinqualitylabelsall models 2nqg, resolution 2.04Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Calpain 1 proteolytic core inactivated by WR18(S,S), an epoxysuccinyl-type inhibitor.

Overview

Calpains are calcium-dependent proteases that are required for numerous, intracellular processes but also play an important role in the development, of pathologies such as ischemic injury and neurodegeneration. Many current, small molecule calpain inhibitors also inhibit other cysteine proteases, including cathepsins, and need improved selectivity. The specificity of, inhibition of several calpains and papain was profiled using synthetic, positional scanning libraries of epoxide-based compounds that target the, active-site cysteine. These peptidomimetic libraries probe the P4, P3, and, P2 positions, display (S,S)- or (R,R)-epoxide stereochemistries, and, incorporate both natural and non-natural amino acids. To facilitate, library screening, an SDS-PAGE assay that measures the extent of, hydrolysis of an inactive recombinant m-calpain was developed. Individual, epoxide inhibitors were synthesized guided by calpain-specific preferences, observed from the profiles and tested for inhibition against calpain. The, most potent compounds were assayed for specificity against cathepsins B, L, and K. Several compounds demonstrated high inhibition specificity for, calpains over cathepsins. The best of these inhibitors, WRH(R,R), irreversibly inactivates m- and mu-calpain rapidly (k(2)/K(i) = 131,000, and 16,500 m(-1) s(-1), respectively) but behaves exclusively as a, reversible and less potent inhibitor toward the cathepsins. X-ray, crystallography of the proteolytic core of rat mu-calpain inactivated by, the epoxide compounds WR gamma-cyano-alpha-aminobutyric acid (S,S) and WR, allylglycine (R,R) reveals that the stereochemistry of the epoxide, influences positioning and orientation of the P2 residue, facilitating, alternate interactions within the S2 pocket. Moreover, the WR, gamma-cyano-alpha-aminobutyric acid (S,S)-complexed structure defines a, novel hydrogen-bonding site within the S2 pocket of calpains.

About this Structure

2NQG is a Single protein structure of sequence from Rattus norvegicus with CA and NQG as ligands. Active as Calpain-1, with EC number 3.4.22.52 Full crystallographic information is available from OCA.

Reference

Development of calpain-specific inactivators by screening of positional scanning epoxide libraries., Cuerrier D, Moldoveanu T, Campbell RL, Kelly J, Yoruk B, Verhelst SH, Greenbaum D, Bogyo M, Davies PL, J Biol Chem. 2007 Mar 30;282(13):9600-11. Epub 2007 Jan 11. PMID:17218315

Page seeded by OCA on Wed Nov 21 12:50:47 2007