2a4o
From Proteopedia
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|PDB= 2a4o |SIZE=350|CAPTION= <scene name='initialview01'>2a4o</scene>, resolution 1.55Å | |PDB= 2a4o |SIZE=350|CAPTION= <scene name='initialview01'>2a4o</scene>, resolution 1.55Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=BBL:N-[(BENZYLOXY)CARBONYL]-L-ALANINE'>BBL</scene> | + | |LIGAND= <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=BBL:N-[(BENZYLOXY)CARBONYL]-L-ALANINE'>BBL</scene>, <scene name='pdbligand=NFA:PHENYLALANINE+AMIDE'>NFA</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Picornain_3C Picornain 3C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.28 3.4.22.28] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Picornain_3C Picornain 3C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.28 3.4.22.28] </span> |
|GENE= 3C ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=12092 Hepatitis A virus]) | |GENE= 3C ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=12092 Hepatitis A virus]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1hav|1HAV]], [[1qa7|1QA7]], [[2cxv|2CXV]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2a4o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a4o OCA], [http://www.ebi.ac.uk/pdbsum/2a4o PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2a4o RCSB]</span> | ||
}} | }} | ||
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[[Category: Vederas, J C.]] | [[Category: Vederas, J C.]] | ||
[[Category: Yin, J.]] | [[Category: Yin, J.]] | ||
| - | [[Category: BBL]] | ||
[[Category: beta barrel]] | [[Category: beta barrel]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 01:47:48 2008'' |
Revision as of 22:47, 30 March 2008
| |||||||
| , resolution 1.55Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , | ||||||
| Gene: | 3C (Hepatitis A virus) | ||||||
| Activity: | Picornain 3C, with EC number 3.4.22.28 | ||||||
| Related: | 1HAV, 1QA7, 2CXV
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Dual modes of modification of Hepatitis A virus 3C protease by a serine derived beta-lactone: selective crytstallization and high resolution structure of the His102 adduct
Overview
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.
About this Structure
2A4O 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
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