1MS6

Dipeptide Nitrile Inhibitor Bound to Cathepsin S.

Summary for 1MS6

• Entry DOI: 10.2210/pdb1ms6/pdb
• Descriptor: Cathepsin S, MORPHOLINE-4-CARBOXYLIC ACID [1S-(2-BENZYLOXY-1R-CYANO-ETHYLCARBAMOYL)-3-METHYL-BUTYL]AMIDE (2 entities in total)
• Functional Keywords: hydrolase, cathepsin, protease
• Biological source: Homo sapiens (human)
• Cellular location: Lysosome: P25774
• Total number of polymer chains: 1
• Total formula weight: 25100.16

Authors

Ward, Y.D.,Thomson, D.S.,Frye, L.L.,Cywin, C.L.,Morwick, T.,Emmanuel, M.J.,Zindell, R.,McNeil, D.,Bekkali, Y.,Giradot, M.,Hrapchak, M.,DeTuri, M.,Crane, K.,White, D.,Pav, S.,Wang, Y.,Hao, M.H.,Grygon, C.A.,Labadia, M.E.,Freeman, D.M.,Davidson, W.,Hopkins, J.L.,Brown, M.L.,Spero, D.M. (deposition date: 2002-09-19, release date: 2003-04-22, Last modification date: 2024-12-25)

Primary citation

Ward, Y.D.,Thomson, D.S.,Frye, L.L.,Cywin, C.L.,Morwick, T.,Emmanuel, M.J.,Zindell, R.,McNeil, D.,Bekkali, Y.,Giradot, M.,Hrapchak, M.,DeTuri, M.,Crane, K.,White, D.,Pav, S.,Wang, Y.,Hao, M.H.,Grygon, C.A.,Labadia, M.E.,Freeman, D.M.,Davidson, W.,Hopkins, J.L.,Brown, M.L.,Spero, D.M.
Design and synthesis of dipeptide nitriles as reversible and potent Cathepsin S inhibitors
J.Med.Chem., 45:5471-5482, 2002

PubMed Abstract: The specificity of the immune response relies on processing of foreign proteins and presentation of antigenic peptides at the cell surface. Inhibition of antigen presentation, and the subsequent activation of T-cells, should, in theory, modulate the immune response. The cysteine protease Cathepsin S performs a fundamental step in antigen presentation and therefore represents an attractive target for inhibition. Herein, we report a series of potent and reversible Cathepsin S inhibitors based on dipeptide nitriles. These inhibitors show nanomolar inhibition of the target enzyme as well as cellular potency in a human B cell line. The first X-ray crystal structure of a reversible inhibitor cocrystallized with Cathepsin S is also reported.

PubMed: 12459015
DOI: 10.1021/jm020209i

Experimental method

X-RAY DIFFRACTION (1.9 Å)