3CJ2

Crystal structure of hepatitis c virus rna-dependent rna polymerase ns5b in complex with optimized small molecule fragments

Summary for 3CJ2

• Entry DOI: 10.2210/pdb3cj2/pdb
• Related: 3CIZ 3CJ0 3CJ3 3CJ4 3CJ5
• Descriptor: RNA-directed RNA polymerase, NICKEL (II) ION, 4-bromo-2-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]carbonyl}aniline, ... (4 entities in total)
• Functional Keywords: drug discovery, hcv ns5b, fragment based, acetylation, apoptosis, atp-binding, capsid protein, 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
• Biological source: Hepatitis C virus subtype 1b
• 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: 129093.12

Authors

Kissinger, c. (deposition date: 2008-03-12, release date: 2008-04-15, Last modification date: 2024-10-30)

Primary citation

Antonysamy, S.S.,Aubol, B.,Blaney, J.,Browner, M.F.,Giannetti, A.M.,Harris, S.F.,Hebert, N.,Hendle, J.,Hopkins, S.,Jefferson, E.,Kissinger, C.,Leveque, V.,Marciano, D.,McGee, E.,Najera, I.,Nolan, B.,Tomimoto, M.,Torres, E.,Wright, T.
Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors.
Bioorg.Med.Chem.Lett., 18:2990-2995, 2008

PubMed Abstract: Non-nucleoside inhibitors of HCV NS5b RNA polymerase were discovered by a fragment-based lead discovery approach, beginning with crystallographic fragment screening. The NS5b binding affinity and biochemical activity of fragment hits and inhibitors was determined by surface plasmon resonance (Biacore) and an enzyme inhibition assay, respectively. Crystallographic fragment screening hits with approximately 1-10mM binding affinity (K(D)) were iteratively optimized to give leads with approximately 200nM biochemical activity and low microM cellular activity in a Replicon assay.

PubMed: 18400495
DOI: 10.1016/j.bmcl.2008.03.056

Experimental method

X-RAY DIFFRACTION (1.75 Å)