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1gmy
From Proteopedia
| 1gmy, resolution 1.90Å () | |||||||||
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| Sites: | |||||||||
| Ligands: | , , | ||||||||
| Activity: | Cathepsin B, with EC number 3.4.22.1 | ||||||||
| Domains: | Peptidase_C1A_CathepsinB | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
CATHEPSIN B COMPLEXED WITH DIPEPTIDYL NITRILE INHIBITOR
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.
Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design., Greenspan PD, Clark KL, Tommasi RA, Cowen SD, McQuire LW, Farley DL, van Duzer JH, Goldberg RL, Zhou H, Du Z, Fitt JJ, Coppa DE, Fang Z, Macchia W, Zhu L, Capparelli MP, Goldstein R, Wigg AM, Doughty JR, Bohacek RS, Knap AK, J Med Chem. 2001 Dec 20;44(26):4524-34. PMID:11741472
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
1GMY is a 3 chains structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
- Greenspan PD, Clark KL, Tommasi RA, Cowen SD, McQuire LW, Farley DL, van Duzer JH, Goldberg RL, Zhou H, Du Z, Fitt JJ, Coppa DE, Fang Z, Macchia W, Zhu L, Capparelli MP, Goldstein R, Wigg AM, Doughty JR, Bohacek RS, Knap AK. Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design. J Med Chem. 2001 Dec 20;44(26):4524-34. PMID:11741472
Page seeded by OCA on Tue Feb 17 19:04:31 2009
Categories: Cathepsin B | Homo sapiens | Bohacek, R S. | Capparelli, M P. | Clark, K L. | Coppa, D E. | Cowen, S D. | Doughty, J R. | Du, Z. | Duzer, J H.Van. | Fang, Z. | Farley, D L. | Fitt, J J. | Goldberg, R L. | Goldstein, R. | Greenspan, P D. | Knap, A K. | Macchia, W. | Mcquire, L W. | Tommasi, R A. | Wigg, A M. | Zhou, H. | Zhu, L. | Cathepsin b | Covalent complex | Hydrolase | Protease | Thiol protease
