From Proteopedia
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| | {{STRUCTURE_2cxv| PDB=2cxv | SCENE= }} | | {{STRUCTURE_2cxv| PDB=2cxv | SCENE= }} |
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| - | '''Dual Modes of Modification of Hepatitis A Virus 3C Protease by a Serine-Derived betaLactone: Selective Crystallization and High-resolution Structure of the His-102 Adduct'''
| + | ===Dual Modes of Modification of Hepatitis A Virus 3C Protease by a Serine-Derived betaLactone: Selective Crystallization and High-resolution Structure of the His-102 Adduct=== |
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| - | ==Overview==
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| - | Hepatitis A virus (HAV) 3C proteinase is a member of the picornain cysteine proteases responsible for the processing of the viral polyprotein, a function essential for viral maturation and infectivity. This and its structural similarity to other 3C and 3C-like proteases make it an attractive target for the development of antiviral drugs. Previous solution NMR studies have shown that a Cys24Ser (C24S) variant of HAV 3C protein, which displays catalytic properties indistinguishable from the native enzyme, is irreversibly inactivated by N-benzyloxycarbonyl-l-serine-beta-lactone (1a) through alkylation of the sulfur atom at the active site Cys172. However, crystallization of an enzyme-inhibitor adduct from the reaction mixture followed by X-ray structural analysis shows only covalent modification of the epsilon2-nitrogen of the surface His102 by the beta-lactone with no reaction at Cys172. Re-examination of the heteronuclear multiple quantum coherence (HMQC) NMR spectra of the enzyme-inhibitor mixture indicates that dual modes of single covalent modification occur with a >/=3:1 ratio of S-alkylation of Cys172 to N-alkylation of His102. The latter product crystallizes readily, probably due to the interaction between the phenyl ring of the N-benzyloxycarbonyl (N-Cbz) moiety and a hydrophobic pocket of a neighboring protein molecule in the crystal. Furthermore, significant structural changes are observed in the active site of the 3C protease, which lead to the formation of a functional catalytic triad with Asp84 accepting one hydrogen bond from His44. Although the 3C protease modified at Cys172 is catalytically inactive, the singly modified His102 N(epsilon2)-alkylated protein displays a significant level of enzymatic activity, which can be further modified/inhibited by N-iodoacetyl-valine-phenylalanine-amide (IVF) (in solution and in crystal) or excessive amount of the same beta-lactone inhibitor (in solution). The success of soaking IVF into HAV 3C-1a crystals demonstrates the usefulness of this new crystal form in the study of enzyme-inhibitor interactions in the proteolytic active site.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_16288920}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 16288920 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_16288920}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Inhibitor]] | | [[Category: Inhibitor]] |
| | [[Category: Picornavirus]] | | [[Category: Picornavirus]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 23:19:11 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 09:51:22 2008'' |
Revision as of 06:51, 29 July 2008
Template:STRUCTURE 2cxv
Dual Modes of Modification of Hepatitis A Virus 3C Protease by a Serine-Derived betaLactone: Selective Crystallization and High-resolution Structure of the His-102 Adduct
Template:ABSTRACT PUBMED 16288920
About this Structure
2CXV is a Single protein structure of sequence from Hepatitis a virus. Full crystallographic information is available from OCA.
Reference
Dual modes of modification of hepatitis A virus 3C protease by a serine-derived beta-lactone: selective crystallization and formation of a functional catalytic triad in the active site., Yin J, Bergmann EM, Cherney MM, Lall MS, Jain RP, Vederas JC, James MN, J Mol Biol. 2005 Dec 9;354(4):854-71. Epub 2005 Oct 14. PMID:16288920
Page seeded by OCA on Tue Jul 29 09:51:22 2008
