1nqc

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{{STRUCTURE_1nqc| PDB=1nqc | SCENE= }}
{{STRUCTURE_1nqc| PDB=1nqc | SCENE= }}
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'''Crystal structures of Cathepsin S inhibitor complexes'''
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===Crystal structures of Cathepsin S inhibitor complexes===
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==Overview==
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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.
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(as it appears on PubMed at http://www.pubmed.gov), where 12641451 is the PubMed ID number.
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{{ABSTRACT_PUBMED_12641451}}
==About this Structure==
==About this Structure==
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[[Category: Structural plasticity]]
[[Category: Structural plasticity]]
[[Category: Structure-based design]]
[[Category: Structure-based design]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 02:51:15 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 07:32:51 2008''

Revision as of 04:32, 29 July 2008

Image:1nqc.png

Template:STRUCTURE 1nqc

Crystal structures of Cathepsin S inhibitor complexes

Template:ABSTRACT PUBMED 12641451

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 Tue Jul 29 07:32:51 2008

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