5TRK

CRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS NS5B RNA- DEPENDENT RNA POLYMERASE IN COMPLEX WITH N-{3-[(benzenecarbonyl)amino]-4-[(4-chlorophenyl)methoxy]benzene-1-carbonyl}glycine

Summary for 5TRK

• Entry DOI: 10.2210/pdb5trk/pdb
• Related: 5TRH 5TRI 5TRJ
• Descriptor: Genome polyprotein, (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid, N-{3-[(benzenecarbonyl)amino]-4-[(4-chlorophenyl)methoxy]benzene-1-carbonyl}glycine, ... (5 entities in total)
• Functional Keywords: ns5b, polymerase, hcv, fingers, palm, thumb, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Hepatitis C virus (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 : Q9WMX2
• Total number of polymer chains: 2
• Total formula weight: 131022.85

Authors

Sheriff, S. (deposition date: 2016-10-26, release date: 2016-11-30, Last modification date: 2023-10-04)

Primary citation

Parcella, K.,Nickel, A.,Beno, B.R.,Sheriff, S.,Wan, C.,Wang, Y.K.,Roberts, S.B.,Meanwell, N.A.,Kadow, J.F.
Discovery and initial optimization of alkoxyanthranilic acid derivatives as inhibitors of HCV NS5B polymerase.
Bioorg. Med. Chem. Lett., 27:295-298, 2017

PubMed Abstract: Alkoxyanthranilic acid derivatives have been identified to inhibit HCV NS5B polymerase, binding in an allosteric site located at the convergence of the palm and thumb regions. Information from co-crystal structures guided the structural design strategy. Ultimately, two independent structural modifications led to a similar shift in binding mode that when combined led to a synergistic improvement in potency and the identification of inhibitors with sub-micromolar HCV NS5B binding potency.

PubMed: 27908764
DOI: 10.1016/j.bmcl.2016.11.054

Experimental method

X-RAY DIFFRACTION (2.06 Å)