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2nqi

From Proteopedia

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{{STRUCTURE_2nqi| PDB=2nqi | SCENE= }}
{{STRUCTURE_2nqi| PDB=2nqi | SCENE= }}
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'''Calpain 1 proteolytic core inactivated by WR13(R,R), an epoxysuccinyl-type inhibitor.'''
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===Calpain 1 proteolytic core inactivated by WR13(R,R), an epoxysuccinyl-type inhibitor.===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_17218315}}
==About this Structure==
==About this Structure==
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[[Category: Protease]]
[[Category: Protease]]
[[Category: Proteinase]]
[[Category: Proteinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 09:47:02 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 13:42:56 2008''

Revision as of 10:42, 27 July 2008

Image:2nqi.png

Template:STRUCTURE 2nqi

Calpain 1 proteolytic core inactivated by WR13(R,R), an epoxysuccinyl-type inhibitor.

Template:ABSTRACT PUBMED 17218315

About this Structure

2NQI is a Single protein structure of sequence from Rattus norvegicus. 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 Sun Jul 27 13:42:56 2008

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