PDBsum entry 4oks

Hydrolase/hydrolase inhibitor

PDB id: 4oks

Contents

Protein chains

440 a.a.

Ligands

2T9

Metals

_CA ×2

Waters ×268

PDB id:

4oks

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of hepatitis c virus ns3 helicase inhibitor co- complex with compound 19 [[6-(3,5-diaminophenyl)-1-(2-methoxy-5- nitrobenzyl)-1h-indol-3-yl]acetic acid]

Structure:

Serine protease ns3. Chain: a, b. Fragment: unp residues 1206-1656. Engineered: yes

Source:

Hepatitis c virus. Organism_taxid: 11103. Gene: ns3. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.25Å R-factor: 0.207 R-free: 0.258

Authors:

A.K.Padyana

Key ref:

S.R.LaPlante et al. (2014). Integrated strategies for identifying leads that target the NS3 helicase of the hepatitis C virus. J Med Chem, 57, 2074-2090. PubMed id: 24467709 DOI: 10.1021/jm401432c

Date:

22-Jan-14 Release date: 05-Mar-14

Protein chains

K4KA16  (K4KA16_9HEPC) -  Genome polyprotein (Fragment) from Hepacivirus hominis

Seq: 2939 a.a.

Struc: 440 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.3.4.21.98 - hepacivirin.
• Reaction: Hydrolysis of four peptide bonds in the viral precursor polyprotein, commonly with Asp or Glu in the P6 position, Cys or Thr in P1 and Ser or Ala in P1'.
• Enzyme class 2: E.C.3.6.1.15 - nucleoside-triphosphate phosphatase.
• Reaction: a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-diphosphate + phosphate + H⁺
• Enzyme class 3: E.C.3.6.4.13 - Rna helicase.
• Reaction: ATP + H2O = ADP + phosphate + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm401432c

J Med Chem 57:2074-2090 (2014)

PubMed id: 24467709

Integrated strategies for identifying leads that target the NS3 helicase of the hepatitis C virus.

S.R.LaPlante, A.K.Padyana, A.Abeywardane, P.Bonneau, M.Cartier, R.Coulombe, A.Jakalian, J.Wildeson-Jones, X.Li, S.Liang, G.McKercher, P.White, Q.Zhang, S.J.Taylor.

ABSTRACT

Future treatments for individuals infected by the hepatitis C virus (HCV) will likely involve combinations of compounds that inhibit multiple viral targets. The helicase of HCV is an attractive target with no known drug candidates in clinical trials. Herein we describe an integrated strategy for identifying fragment inhibitors using structural and biophysical techniques. Based on an X-ray structure of apo HCV helicase and in silico and bioinformatic analyses of HCV variants, we identified that one site in particular (labeled 3 + 4) was the most conserved and attractive pocket to target for a drug discovery campaign. Compounds from multiple sources were screened to identify inhibitors or binders to this site, and enzymatic and biophysical assays (NMR and SPR) were used to triage the most promising ligands for 3D structure determination by X-ray crystallography. Medicinal chemistry and biophysical evaluations focused on exploring the most promising lead series. The strategies employed here can have general utility in drug discovery.