3GNW

HCV NS5B polymerase in complex with 1,5 benzodiazepine inhibitor 4c

Summary for 3GNW

• Entry DOI: 10.2210/pdb3gnw/pdb
• Related: 3CSO 3GNV 3GOL
• Descriptor: RNA-directed RNA polymerase, (11S)-11-[4-(benzyloxy)-2-fluorophenyl]-3,3-dimethyl-10-[(6-methylpyridin-2-yl)carbonyl]-2,3,4,5,10,11-hexahydrothiopyrano[3,2-b][1,5]benzodiazepin-6-ol 1,1-dioxide, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: 1, 5-benzodiazepines, hepatitis c virus, ns5b, polymerase, sulfone, apoptosis, atp-binding, capsid protein, cell membrane, endoplasmic reticulum, envelope protein, fusion protein, glycoprotein, helicase, host-virus interaction, hydrolase, interferon antiviral system evasion, lipid droplet, lipoprotein, membrane, metal-binding, mitochondrion, multifunctional enzyme, nucleotide-binding, nucleotidyltransferase, nucleus, oncogene, palmitate, phosphoprotein, protease, ribonucleoprotein, rna replication, rna-binding, rna-directed rna polymerase, secreted, serine protease, sh3-binding, thiol protease, transcription, transcription regulation, transferase, transmembrane, viral nucleoprotein, virion
• Biological source: Hepatitis C virus isolate (HCV)
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane ; Single-pass membrane protein . Core protein p19: Virion . Envelope glycoprotein E1: Virion membrane ; Single-pass type I membrane protein . Envelope glycoprotein E2: Virion membrane ; Single-pass type I membrane protein . p7: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Protease NS2-3: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Serine protease NS3: Host endoplasmic reticulum membrane ; Peripheral membrane protein . Non-structural protein 4A: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein . Non-structural protein 4B: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Non-structural protein 5A: Host endoplasmic reticulum membrane ; Peripheral membrane protein . RNA-directed RNA polymerase: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein : O92972
• Total number of polymer chains: 2
• Total formula weight: 130968.28

Authors

Nyanguile, O.,De Bondt, H. (deposition date: 2009-03-18, release date: 2009-10-20, Last modification date: 2023-11-01)

Primary citation

Vandyck, K.,Cummings, M.D.,Nyanguile, O.,Boutton, C.W.,Vendeville, S.,McGowan, D.,Devogelaere, B.,Amssoms, K.,Last, S.,Rombauts, K.,Tahri, A.,Lory, P.,Hu, L.,Beauchamp, D.A.,Simmen, K.,Raboisson, P.
Structure-based design of a benzodiazepine scaffold yields a potent allosteric inhibitor of hepatitis C NS5B RNA polymerase.
J.Med.Chem., 52:4099-4102, 2009

PubMed Abstract: HCV NS5B polymerase, an essential and virus-specific enzyme, is an important target for drug discovery. Using structure-based design, we optimized a 1,5-benzodiazepine NS5B polymerase inhibitor chemotype into a new sulfone-containing scaffold. The design yielded potent inhibitor (S)-4c (K(D) = 0.79 nM), which has approximately 20-fold greater affinity for NS5B than its carbonyl analogue (R)-2c.

PubMed: 19507864
DOI: 10.1021/jm9005548

Experimental method

X-RAY DIFFRACTION (2.39 Å)