PDBsum entry 4jvq

Hydrolase/hydrolase inhibitor

PDB id: 4jvq

Contents

Protein chains

560 a.a.

Ligands

GOL ×2

1ML ×2

Metals

_MG ×4

Waters ×705

PDB id:

4jvq

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of hcv ns5b polymerase in complex with compound 9

Structure:

Genome polyprotein. Chain: a, b. Fragment: RNA-directed RNA polymerase, unp residues 2420-2989. Synonym: core protein p21, capsid protein c, p21, core protein p19, envelope glycoprotein e1, gp32, gp35, envelope glycoprotein e2, ns1, gp68, gp70, p7, protease ns2-3, p23, serine protease ns3, hepacivirin, ns3p, p70, non-structural protein 4a, ns4a, p8, non- structural protein 4b, ns4b, p27, non-structural protein 5a, ns5a, p56, RNA-directed RNA polymerase, ns5b, p68.

Source:

Hepatitis c virus. Hcv. Organism_taxid: 420174. Strain: 1bj4. Gene: ns5b. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.40Å R-factor: 0.185 R-free: 0.226

Authors:

R.Coulombe

Key ref:

S.R.LaPlante et al. (2014). Enantiomeric atropisomers inhibit HCV polymerase and/or HIV matrix: characterizing hindered bond rotations and target selectivity. J Med Chem, 57, 1944-1951. PubMed id: 24024973 DOI: 10.1021/jm401202a

Date:

26-Mar-13 Release date: 05-Feb-14

Protein chains

O92972  (POLG_HCVJ4) -  Genome polyprotein from Hepatitis C virus genotype 1b (strain HC-J4)

Seq: 3010 a.a.

Struc: 560 a.a.

Enzyme reactions

• Enzyme class 1: E.C.2.7.7.48 - RNA-directed Rna polymerase.
• Reaction: RNA(n) + a ribonucleoside 5'-triphosphate = RNA(n+1) + diphosphate
• Enzyme class 2: 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 3: E.C.3.6.1.15 - nucleoside-triphosphate phosphatase.
• Reaction: a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-diphosphate + phosphate + H⁺
• Enzyme class 4: 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/jm401202a

J Med Chem 57:1944-1951 (2014)

PubMed id: 24024973

Enantiomeric atropisomers inhibit HCV polymerase and/or HIV matrix: characterizing hindered bond rotations and target selectivity.

S.R.LaPlante, P.Forgione, C.Boucher, R.Coulombe, J.Gillard, O.Hucke, A.Jakalian, M.A.Joly, G.Kukolj, C.Lemke, R.McCollum, S.Titolo, P.L.Beaulieu, T.Stammers.

ABSTRACT

An anthranilic acid series of allosteric thumb pocket 2 HCV NS5B polymerase inhibitors exhibited hindered rotation along a covalent bond axis, and the existence of atropisomer chirality was confirmed by NMR, HPLC analysis on chiral supports, and computational studies. A thorough understanding of the concerted rotational properties and the influence exerted by substituents involved in this steric phenomenon was attained through biophysical studies on a series of truncated analogues. The racemization half-life of a compound within this series was determined to be 69 min, which was consistent with a class 2 atropisomer (intermediate conformational exchange). It was further found by X-ray crystallography that one enantiomer of a compound bound to the intended HCV NS5B polymerase target whereas the mirror image atropisomer was able to bind to an unrelated HIV matrix target. Analogues were then identified that selectively inhibited the former. These studies highlight that atropisomer chirality can lead to distinct entities with specific properties, and the phenomenon of atropisomerism in drug discovery should be evaluated and appropriately managed.