1nqc
From Proteopedia
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'''Crystal structures of Cathepsin S inhibitor complexes''' | '''Crystal structures of Cathepsin S inhibitor complexes''' | ||
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[[Category: Sulea, T.]] | [[Category: Sulea, T.]] | ||
[[Category: Wang, I K.]] | [[Category: Wang, I K.]] | ||
| - | [[Category: | + | [[Category: Antigen presentation]] |
| - | [[Category: | + | [[Category: Binding specificity]] |
| - | [[Category: | + | [[Category: Cysteine protease]] |
| - | [[Category: | + | [[Category: Inhibitor complex]] |
| - | [[Category: | + | [[Category: Structural plasticity]] |
| - | [[Category: | + | [[Category: Structure-based design]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 02:51:15 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 23:51, 2 May 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. 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 Page seeded by OCA on Sat May 3 02:51:15 2008
Categories: Cathepsin S | Homo sapiens | Single protein | Ammirati, M. | Cygler, M. | Danley, D E. | Griffor, M C. | Kamath, A V. | Laird, E R. | Menard, R. | Pauly, T A. | Rath, V L. | Sivaraman, J. | Sulea, T. | Wang, I K. | Antigen presentation | Binding specificity | Cysteine protease | Inhibitor complex | Structural plasticity | Structure-based design
