› 4nld

X-ray diffraction
2.75Å resolution

Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with BMS-791325 also known as (1aR,12bS)-8-cyclohexyl-n-(dimethylsulfamoyl)-11-methoxy-1a-{[(1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide and 2-(4-fluorophenyl)-n-methyl-6-[(methylsulfonyl)amino]-5-(propan-2-yloxy)-1-benzofuran-3-carboxamide

Released:
DOI: 10.2210/pdb4nld/pdb
PDB entry 4nld coloured by chain, front view.
PDB entry 4nld coloured by chain, side view.
PDB entry 4nld coloured by chain, top view.
Source organism: Hepatitis C virus (isolate Con1)
Primary publication:
Discovery and preclinical characterization of the cyclopropylindolobenzazepine BMS-791325, a potent allosteric inhibitor of the hepatitis C virus NS5B polymerase.
Gentles RG, Ding M, Bender JA, Bergstrom CP, Grant-Young K, Hewawasam P, Hudyma T, Martin S, Nickel A, Regueiro-Ren A, Tu Y, Yang Z, Yeung KS, Zheng X, Chao S, Sun JH, Beno BR, Camac DM, Chang CH, Gao M, Morin PE, Sheriff S, Tredup J, Wan J, Witmer MR, Xie D, Hanumegowda U, Knipe J, Mosure K, Santone KS, Parker DD, Zhuo X, Lemm J, Liu M, Pelosi L, Rigat K, Voss S, Wang Y, Wang YK, Colonno RJ, Gao M, Roberts SB, Gao Q, Ng A, Meanwell NA, Kadow JF
J Med Chem 57 1855-79 (2014)
PMID: 24397558

Function and Biology Details

Reactions catalysed: 
Nucleoside triphosphate + RNA(n) = diphosphate + RNA(n+1)
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'.
NTP + H(2)O = NDP + phosphate
ATP + H(2)O = ADP + phosphate
Biochemical function:
Biological process:
Cellular component:
  • not assigned
Sequence domains:

Structure analysis Details

Assembly composition:
monomeric (preferred)
Assembly name:
PDBe Complex ID:
PDB-CPX-194373 (preferred)
Entry contents:
1 distinct polypeptide molecule
Macromolecule:
RNA-directed RNA polymerase Chain: A
Molecule details ›
Chain: A
Length: 574 amino acids
Theoretical weight: 63.96 KDa
Source organism: Hepatitis C virus (isolate Con1)
Expression system: Escherichia coli BL21(DE3)
UniProt:
  • Canonical: Q9WMX2 (Residues: 2420-2992; Coverage: 19%)
Sequence domains: Viral RNA dependent RNA polymerase
Structure domains: Alpha-Beta Plaits

Ligands and Environments

4 bound ligands:
Ligand 2N7 1 x 2N7
Ligand 2N5 1 x 2N5
Ligand SO4 4 x SO4
Ligand BOG 2 x BOG
No modified residues

Experiments and Validation Details

Entry percentile scores
X-ray source: APS BEAMLINE 17-ID
Spacegroup: I222
Unit cell:
a: 73Å b: 120.6Å c: 201.5Å
α: 90° β: 90° γ: 90°
R-values:
R R work R free
0.215 0.213 0.253
Expression system: Escherichia coli BL21(DE3)

Quick links

Citations

4 review citations

Indoles as therapeutics of interest in medicinal chemistry: Bird's eye view.
Chadha et al. (2017)
3 more

6 mentions without citation

Approved Antiviral Drugs over the Past 50 Years.
De Clercq et al. (2016)
5 more