3FRZ

Crystal Structure of HCV NS5B RNA polymerase in complex with PF868554

3FRZ の概要

• エントリーDOI: 10.2210/pdb3frz/pdb
• 関連するPDBエントリー: 1OS5 2HAI
• 分子名称: RNA-directed RNA polymerase, (6R)-6-cyclopentyl-6-[2-(2,6-diethylpyridin-4-yl)ethyl]-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one, N-[(benzyloxy)carbonyl]-L-alpha-glutamyl-N-[(1S)-4-oxo-4-phenyl-1-propylbut-2-en-1-yl]-L-phenylalaninamide, ... (5 entities in total)
• 機能のキーワード: viral polymerase, acetylation, apoptosis, atp-binding, capsid protein, cell membrane, cytoplasm, 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, ubl conjugation, viral nucleoprotein, virion, zinc
• 由来する生物種: Hepatitis C virus
• 細胞内の位置: 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
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 65373.89

構造登録者

Parge, H.E. (登録日: 2009-01-08, 公開日: 2009-03-10, 最終更新日: 2021-10-20)

主引用文献

Li, H.,Tatlock, J.,Linton, A.,Gonzalez, J.,Jewell, T.,Patel, L.,Ludlum, S.,Drowns, M.,Rahavendran, S.V.,Skor, H.,Hunter, R.,Shi, S.T.,Herlihy, K.J.,Parge, H.,Hickey, M.,Yu, X.,Chau, F.,Nonomiya, J.,Lewis, C.
Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor.
J.Med.Chem., 52:1255-1258, 2009

PubMed Abstract: The HCV RNA-dependent RNA polymerase has emerged as one of the key targets for novel anti-HCV therapy development. Herein, we report the optimization of the dihydropyrone series inhibitors to improve compound aqueous solubility and reduce CYP2D6 inhibition, which led to the discovery of compound 24 (PF-00868554). Compound 24 is a potent and selective HCV polymerase inhibitor with a favorable pharmacokinetic profile and has recently entered a phase II clinical evaluation in patients with genotype 1 HCV.

PubMed: 19209845
DOI: 10.1021/jm8014537

実験手法

X-RAY DIFFRACTION (1.86 Å)