› 4nwk

X-ray diffraction
1.62Å resolution

Crystal structure of hepatis c virus protease (ns3) complexed with bms-605339 aka n-(tert-butoxycarbonyl)-3-me thyl-l-valyl-(4r)-n-((1r,2s)-1-((cyclopropylsulfonyl)carba moyl)-2-vinylcyclopropyl)-4-((6-methoxy-1-isoquinolinyl)ox y)-l-prolinamide

Released:
DOI: 10.2210/pdb4nwk/pdb
PDB entry 4nwk coloured by chain, front view.
PDB entry 4nwk coloured by chain, side view.
PDB entry 4nwk coloured by chain, top view.
Source organism: hepatitis C virus genotype 1a
Primary publication:
Discovery and early clinical evaluation of BMS-605339, a potent and orally efficacious tripeptidic acylsulfonamide NS3 protease inhibitor for the treatment of hepatitis C virus infection.
Scola PM, Wang AX, Good AC, Sun LQ, Combrink KD, Campbell JA, Chen J, Tu Y, Sin N, Venables BL, Sit SY, Chen Y, Cocuzza A, Bilder DM, D'Andrea S, Zheng B, Hewawasam P, Ding M, Thuring J, Li J, Hernandez D, Yu F, Falk P, Zhai G, Sheaffer AK, Chen C, Lee MS, Barry D, Knipe JO, Li W, Han YH, Jenkins S, Gesenberg C, Gao Q, Sinz MW, Santone KS, Zvyaga T, Rajamani R, Klei HE, Colonno RJ, Grasela DM, Hughes E, Chien C, Adams S, Levesque PC, Li D, Zhu J, Meanwell NA, McPhee F
J Med Chem 57 1708-29 (2014)
PMID: 24555570

Function and Biology Details

Reactions catalysed: 
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-108606 (preferred)
Entry contents:
1 distinct polypeptide molecule
Macromolecule:
HCV NS3 1a Protease Chain: A
Molecule details ›
Chain: A
Length: 219 amino acids
Theoretical weight: 23.26 KDa
Source organism: hepatitis C virus genotype 1a
Expression system: Escherichia coli
UniProt:
  • Canonical: A8DG50 (Residues: 1013-1026, 1031-1208; Coverage: 6%)
Sequence domains: Hepatitis C virus NS3 protease
Structure domains:

Ligands and Environments

4 bound ligands:
Ligand 2R8 1 x 2R8
Ligand ZN 1 x ZN
Ligand SO4 1 x SO4
Ligand GOL 7 x GOL
No modified residues

Experiments and Validation Details

Entry percentile scores
X-ray source: APS BEAMLINE 32-ID
Spacegroup: P21212
Unit cell:
a: 43.197Å b: 103.852Å c: 45.298Å
α: 90° β: 90° γ: 90°
R-values:
R R work R free
0.199 0.198 0.213
Expression system: Escherichia coli

Quick links

Citations

10 review citations

Current therapy for chronic hepatitis C: The role of direct-acting antivirals.
Li et al. (2017)
9 more

1 mention without citation

The use of small-molecule structures to complement protein-ligand crystal structures in drug discovery.
Groom et al. (2017)