1gmy: Difference between revisions
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==Overview== | ==Overview== | ||
Cathepsin B is a member of the papain superfamily of cysteine proteases, and has been implicated in the pathology of numerous diseases, including, arthritis and cancer. As part of an effort to identify potent, reversible, inhibitors of this protease, we examined a series of dipeptidyl nitriles, starting with the previously reported Cbz-Phe-NH-CH(2)CN (19, IC(50) = 62, microM). High-resolution X-ray crystallographic data and molecular, modeling were used to optimize the P(1), P(2), and P(3) substituents of, this template. Cathepsin B is unique in its class in that it contains a, carboxylate recognition site in the S(2)' pocket of the active site., Inhibitor potency and selectivity were enhanced by tethering a carboxylate, functionality from the carbon alpha to the nitrile to interact with .. | Cathepsin B is a member of the papain superfamily of cysteine proteases, and has been implicated in the pathology of numerous diseases, including, arthritis and cancer. As part of an effort to identify potent, reversible, inhibitors of this protease, we examined a series of dipeptidyl nitriles, starting with the previously reported Cbz-Phe-NH-CH(2)CN (19, IC(50) = 62, microM). High-resolution X-ray crystallographic data and molecular, modeling were used to optimize the P(1), P(2), and P(3) substituents of, this template. Cathepsin B is unique in its class in that it contains a, carboxylate recognition site in the S(2)' pocket of the active site., Inhibitor potency and selectivity were enhanced by tethering a carboxylate, functionality from the carbon alpha to the nitrile to interact with this, region of the enzyme. This resulted in the identification of compound 10, a 7 nM inhibitor of cathepsin B, with excellent selectivity over other, cysteine cathepsins. | ||
==About this Structure== | ==About this Structure== | ||
1GMY is a | 1GMY is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with APD, AEM, DFA, AEM and APD as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Cathepsin_B Cathepsin B], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.1 3.4.22.1] Structure known Active Site: ACT. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1GMY OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: thiol protease]] | [[Category: thiol protease]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 13:40:59 2007'' | ||
