1nqc

From Proteopedia

Revision as of 14:30, 15 February 2008

Crystal structures of Cathepsin S inhibitor complexes

Overview

Cathepsin S, a lysosomal cysteine protease of the papain superfamily, has, been implicated in the preparation of MHC class II alphabeta-heterodimers, for antigen presentation to CD4+ T lymphocytes and is considered a, potential target for autoimmune-disease therapy. Selective inhibition of, this enzyme may be therapeutically useful for attenuating the hyperimmune, responses in a number of disorders. We determined the three-dimensional, crystal structures of human cathepsin S in complex with potent covalent, inhibitors, the aldehyde inhibitor, 4-morpholinecarbonyl-Phe-(S-benzyl)Cys-Psi(CH=O), and the vinyl sulfone, irreversible inhibitor, 4-morpholinecarbonyl-Leu-Hph-Psi(CH=CH-SO(2)-phenyl) at resolutions of 1.8, and 2.0 A, respectively. In the structure of the cathepsin S-aldehyde, complex, the tetrahedral thiohemiacetal adduct favors the S-configuration, in which the oxygen atom interacts with the imidazole group of the active, site His164 rather than with the oxyanion hole. The present structures, provide a detailed map of noncovalent intermolecular interactions, established in the substrate-binding subsites S3 to S1' of cathepsin S. In, the S2 pocket, which is the binding affinity hot spot of cathepsin S, the, Phe211 side chain can assume two stable conformations that accommodate, either the P2-Leu or a bulkier P2-Phe side chain. This structural, plasticity of the S2 pocket in cathepsin S explains the selective, inhibition of cathepsin S over cathepsin K afforded by inhibitors with the, P2-Phe side chain. Comparison with the structures of cathepsins K, V, and, L allows delineation of local intermolecular contacts that are unique to, cathepsin S.

About this Structure

1NQC is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Cathepsin S, with EC number 3.4.22.27 Full crystallographic information is available from OCA.

Reference

Specificity determinants of human cathepsin s revealed by crystal structures of complexes., Pauly TA, Sulea T, Ammirati M, Sivaraman J, Danley DE, Griffor MC, Kamath AV, Wang IK, Laird ER, Seddon AP, Menard R, Cygler M, Rath VL, Biochemistry. 2003 Mar 25;42(11):3203-13. PMID:12641451

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