1GMY

Cathepsin B complexed with dipeptidyl nitrile inhibitor

Summary for 1GMY

• Entry DOI: 10.2210/pdb1gmy/pdb
• Related: 1CSB 1HUC 1PBH 2PBH 3PBH
• Descriptor: CATHEPSIN B, 2-AMINOETHANIMIDIC ACID, 3-METHYLPHENYLALANINE, ... (5 entities in total)
• Functional Keywords: hydrolase/inhibitor, complex (hydrolase-inhibitor), covalent complex, protease, cathepsin b, hydrolase, thiol protease, hydrolase-inhibitor complex
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Lysosome : P07858
• Total number of polymer chains: 3
• Total formula weight: 87812.00

Authors

Greenspan, P.D.,Clark, K.L.,Tommasi, R.A.,Cowen, S.D.,McQuire, L.W.,Farley, D.L.,van Duzer, J.H.,Goldberg, R.L.,Zhou, H.,Du, Z.,Fitt, J.J.,Coppa, D.E.,Fang, Z.,Macchia, W.,Zhu, L.,Capparelli, M.P.,Goldstein, R.,Wigg, A.M.,Doughty, J.R.,Bohacek, R.S.,Knap, A.K. (deposition date: 2001-09-25, release date: 2002-09-19, Last modification date: 2017-07-05)

Primary citation

Greenspan, P.D.,Clark, K.L.,Tommasi, R.A.,Cowen, S.D.,Mcquire, L.W.,Farley, D.L.,Van Duzer, J.H.,Goldberg, R.L.,Zhou, H.,Du, Z.,Fitt, J.J.,Coppa, D.E.,Fang, Z.,Macchia, W.,Zhu, L.,Capparelli, M.P.,Goldstein, R.,Wigg, A.M.,Doughty, J.R.,S Bohacek, R.,Knap, A.K.
Identification of Dipeptidyl Nitriles as Potent and Selective Inhibitors of Cathepsin B Through Structure-Based Drug Design
J.Med.Chem., 44:4524-, 2001

PubMed Abstract: 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.

PubMed: 11741472
DOI: 10.1021/JM010206Q

Experimental method

X-RAY DIFFRACTION (1.9 Å)