3GYN

Crystal structure of HCV NS5B polymerase with a novel monocyclic dihydropyridinone inhibitor

Summary for 3GYN

• Entry DOI: 10.2210/pdb3gyn/pdb
• Related: 3IGV
• Descriptor: RNA-directed RNA polymerase, N-{3-[(5R)-1-cyclopentyl-4-hydroxy-5-methyl-5-(3-methylbutyl)-2-oxo-1,2,5,6-tetrahydropyridin-3-yl]-1,1-dioxido-4H-1,2,4-benzothiadiazin-7-yl}methanesulfonamide (3 entities in total)
• Functional Keywords: protein-ligand complex, rna replication, rna-binding, rna-directed rna polymerase, metal-binding, nucleotide-binding, nucleotidyltransferase, transcription, transferase, acetylation, apoptosis, atp-binding, capsid protein, cell membrane, cytoplasm, disulfide bond, endoplasmic reticulum, envelope protein, fusion protein, glycoprotein, helicase, host-virus interaction, hydrolase, interferon antiviral system evasion, lipid droplet, lipoprotein, membrane, mitochondrion, multifunctional enzyme, nucleus, oncogene, palmitate, phosphoprotein, protease, ribonucleoprotein, secreted, serine protease, sh3-binding, thiol protease, transcription regulation, transmembrane, ubl conjugation, viral nucleoprotein, virion, zinc
• Biological source: Hepatitis C virus (isolate BK) (HCV)
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein. Core protein p19: Virion (By similarity). Envelope glycoprotein E1: Virion membrane; Single-pass type I membrane protein (Potential). Envelope glycoprotein E2: Virion membrane; Single-pass type I membrane protein (Potential). p7: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Protease NS2-3: Host endoplasmic reticulum membrane; Multi-pass membrane protein (Potential). Serine protease NS3: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). Non-structural protein 4A: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential). Non-structural protein 4B: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Non-structural protein 5A: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). RNA-directed RNA polymerase: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential): P26663
• Total number of polymer chains: 2
• Total formula weight: 129768.84

Authors

Zhao, Q.,Showalter, R.E.,Han, Q.,Kissinger, C.R. (deposition date: 2009-04-04, release date: 2009-12-08, Last modification date: 2024-04-03)

Primary citation

Ellis, D.A.,Blazel, J.K.,Tran, C.V.,Ruebsam, F.,Murphy, D.E.,Li, L.S.,Zhao, J.,Zhou, Y.,McGuire, H.M.,Xiang, A.X.,Webber, S.E.,Zhao, Q.,Han, Q.,Kissinger, C.R.,Lardy, M.,Gobbi, A.,Showalter, R.E.,Shah, A.M.,Tsan, M.,Patel, R.A.,LeBrun, L.A.,Kamran, R.,Bartkowski, D.M.,Nolan, T.G.,Norris, D.A.,Sergeeva, M.V.,Kirkovsky, L.
5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of HCV NS5B polymerase.
Bioorg.Med.Chem.Lett., 19:6047-6052, 2009

PubMed Abstract: The discovery of 5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10 microM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed.

PubMed: 19796938
DOI: 10.1016/j.bmcl.2009.09.051

Experimental method

X-RAY DIFFRACTION (2.15 Å)