3HKW

HCV NS5B genotype 1a in complex with 1,5 benzodiazepine inhibitor 6

Summary for 3HKW

• Entry DOI: 10.2210/pdb3hkw/pdb
• Related: 3HKY
• Descriptor: NS5B RNA-dependent RNA polymerase, (11S)-10-[(2,5-dimethyl-1,3-oxazol-4-yl)carbonyl]-11-{2-fluoro-4-[(2-methylprop-2-en-1-yl)oxy]phenyl}-3,3-dimethyl-2,3,4,5,10,11-hexahydrothiopyrano[3,2-b][1,5]benzodiazepin-6-ol 1,1-dioxide, SULFATE ION, ... (5 entities in total)
• Functional Keywords: hcv polymerase, subtype 1a, 1, 5-benzodiazepine, transferase
• Biological source: Hepatitis C virus subtype 1a
• Total number of polymer chains: 3
• Total formula weight: 197081.87

Authors

Nyanguile, O.,De Bondt, H.L. (deposition date: 2009-05-26, release date: 2010-05-26, Last modification date: 2023-11-01)

Primary citation

Nyanguile, O.,Devogelaere, B.,Vijgen, L.,Van den Broeck, W.,Pauwels, F.,Cummings, M.D.,De Bondt, H.L.,Vos, A.M.,Berke, J.M.,Lenz, O.,Vandercruyssen, G.,Vermeiren, K.,Mostmans, W.,Dehertogh, P.,Delouvroy, F.,Vendeville, S.,VanDyck, K.,Dockx, K.,Cleiren, E.,Raboisson, P.,Simmen, K.A.,Fanning, G.C.
1a/1b subtype profiling of nonnucleoside polymerase inhibitors of hepatitis C virus
J.Virol., 84:2923-2934, 2010

PubMed Abstract: The RNA-dependent RNA polymerase (NS5B) of hepatitis C virus (HCV) is an unusually attractive target for drug discovery since it contains five distinct drugable sites. The success of novel antiviral therapies will require nonnucleoside inhibitors to be active in at least patients infected with HCV of subtypes 1a and 1b. Therefore, the genotypic assessment of these agents against clinical isolates derived from genotype 1-infected patients is an important prerequisite for the selection of suitable candidates for clinical development. Here we report the 1a/1b subtype profiling of polymerase inhibitors that bind at each of the four known nonnucleoside binding sites. We show that inhibition of all of the clinical isolates tested is maintained, except for inhibitors that bind at the palm-1 binding site. Subtype coverage varies across chemotypes within this class of inhibitors, and inhibition of genotype 1a improves when hydrophobic contact with the polymerase is increased. We investigated if the polymorphism of the palm-1 binding site is the sole cause of the reduced susceptibility of subtype 1a to inhibition by 1,5-benzodiazepines by using reverse genetics, X-ray crystallography, and surface plasmon resonance studies. We showed Y415F to be a key determinant in conferring resistance on subtype 1a, with this effect being mediated through an inhibitor- and enzyme-bound water molecule. Binding studies revealed that the mechanism of subtype 1a resistance is faster dissociation of the inhibitor from the enzyme.

PubMed: 20071590
DOI: 10.1128/JVI.01980-09

Experimental method

X-RAY DIFFRACTION (1.55 Å)