2fm2
From Proteopedia
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| - | [[Image:2fm2.gif|left|200px]] | + | [[Image:2fm2.gif|left|200px]] |
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| - | '''HCV NS3-4A protease domain complexed with a ketoamide inhibitor, SCH446211''' | + | {{Structure |
| + | |PDB= 2fm2 |SIZE=350|CAPTION= <scene name='initialview01'>2fm2</scene>, resolution 2.70Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene> and <scene name='pdbligand=3BC:TERT-BUTYL [(1S)-1-({(1R,2S,5S)-2-[(3S,10S)-3-(CYCLOPROPYLMETHYL)-12-METHYL-4,5,8,11-TETRAOXO-10-PHENYL-2,6,9,12-TETRAAZATRIDECAN-1-OYL]-6,6-DIMETHYL-3-AZABICYCLO[3.1.0]HEX-3-YL}CARBONYL)-2,2-DIMETHYLPROPYL]CARBAMATE'>3BC</scene> | ||
| + | |ACTIVITY= | ||
| + | |GENE= NS polyprotein ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11103 Hepatitis C virus]) | ||
| + | }} | ||
| + | |||
| + | '''HCV NS3-4A protease domain complexed with a ketoamide inhibitor, SCH446211''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2FM2 is a [ | + | 2FM2 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus Hepatitis c virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FM2 OCA]. |
==Reference== | ==Reference== | ||
| - | Mutations conferring resistance to SCH6, a novel hepatitis C virus NS3/4A protease inhibitor. Reduced RNA replication fitness and partial rescue by second-site mutations., Yi M, Tong X, Skelton A, Chase R, Chen T, Prongay A, Bogen SL, Saksena AK, Njoroge FG, Veselenak RL, Pyles RB, Bourne N, Malcolm BA, Lemon SM, J Biol Chem. 2006 Mar 24;281(12):8205-15. Epub 2005 Dec 13. PMID:[http:// | + | Mutations conferring resistance to SCH6, a novel hepatitis C virus NS3/4A protease inhibitor. Reduced RNA replication fitness and partial rescue by second-site mutations., Yi M, Tong X, Skelton A, Chase R, Chen T, Prongay A, Bogen SL, Saksena AK, Njoroge FG, Veselenak RL, Pyles RB, Bourne N, Malcolm BA, Lemon SM, J Biol Chem. 2006 Mar 24;281(12):8205-15. Epub 2005 Dec 13. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16352601 16352601] |
[[Category: Hepatitis c virus]] | [[Category: Hepatitis c virus]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: ns3/4a protease]] | [[Category: ns3/4a protease]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:54:03 2008'' |
Revision as of 14:54, 20 March 2008
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| , resolution 2.70Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , and | ||||||
| Gene: | NS polyprotein (Hepatitis C virus) | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
HCV NS3-4A protease domain complexed with a ketoamide inhibitor, SCH446211
Overview
Drug resistance is a major issue in the development and use of specific antiviral therapies. Here we report the isolation and characterization of hepatitis C virus RNA replicons resistant to a novel ketoamide inhibitor of the NS3/4A protease, SCH6 (originally SCH446211). Resistant replicon RNAs were generated by G418 selection in the presence of SCH6 in a dose-dependent fashion, with the emergence of resistance reduced at higher SCH6 concentrations. Sequencing demonstrated remarkable consistency in the mutations conferring SCH6 resistance in genotype 1b replicons derived from two different strains of hepatitis C virus, A156T/A156V and R109K. R109K, a novel mutation not reported previously to cause resistance to NS3/4A inhibitors, conferred moderate resistance only to SCH6. Structural analysis indicated that this reflects unique interactions of SCH6 with P'-side residues in the protease active site. In contrast, A156T conferred high level resistance to SCH6 and a related ketoamide, SCH503034, as well as BILN 2061 and VX-950. Unlike R109K, which had minimal impact on NS3/4A enzymatic function, A156T significantly reduced NS3/4A catalytic efficiency, polyprotein processing, and replicon fitness. However, three separate second-site mutations, P89L, Q86R, and G162R, were capable of partially reversing A156T-associated defects in polyprotein processing and/or replicon fitness, without significantly reducing resistance to the protease inhibitor.
About this Structure
2FM2 is a Single protein structure of sequence from Hepatitis c virus. Full crystallographic information is available from OCA.
Reference
Mutations conferring resistance to SCH6, a novel hepatitis C virus NS3/4A protease inhibitor. Reduced RNA replication fitness and partial rescue by second-site mutations., Yi M, Tong X, Skelton A, Chase R, Chen T, Prongay A, Bogen SL, Saksena AK, Njoroge FG, Veselenak RL, Pyles RB, Bourne N, Malcolm BA, Lemon SM, J Biol Chem. 2006 Mar 24;281(12):8205-15. Epub 2005 Dec 13. PMID:16352601
Page seeded by OCA on Thu Mar 20 16:54:03 2008
Categories: Hepatitis c virus | Single protein | Bogen, S L. | Bourne, N. | Chase, R. | Chen, T. | Lemon, S M. | Malcolm, B A. | Njoroge, F G. | Prongay, A. | Pyles, R B. | Saksena, A K. | Skelton, A. | Tong, X. | Veselenak, R L. | Yi, M. | 3BC | BME | ZN | Hcv | Ketoamide inhibitor | Ns3/4a protease
