4JVQ
Crystal structure of hcv ns5b polymerase in complex with compound 9
Summary for 4JVQ
| Entry DOI | 10.2210/pdb4jvq/pdb |
| Related | 3MWV 4JTY 4JTZ 4JU1 4JU2 4JU3 4JU4 4JU6 4JU7 4JVQ 4JY0 4JY1 |
| Descriptor | Genome polyprotein, GLYCEROL, 5-{4-[(4-methoxybenzoyl)amino]phenoxy}-2-{[(trans-4-methylcyclohexyl)carbonyl](propan-2-yl)amino}benzoic acid, ... (5 entities in total) |
| Functional Keywords | rna-directed rna polymerase, transferase, transferase-transferase inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Hepatitis C virus (HCV) |
| Cellular location | Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein (By similarity). 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): O92972 |
| Total number of polymer chains | 2 |
| Total formula weight | 129941.96 |
| Authors | Coulombe, R. (deposition date: 2013-03-26, release date: 2014-02-05, Last modification date: 2023-09-20) |
| Primary citation | Laplante, S.R.,Forgione, P.,Boucher, C.,Coulombe, R.,Gillard, J.,Hucke, O.,Jakalian, A.,Joly, M.A.,Kukolj, G.,Lemke, C.,McCollum, R.,Titolo, S.,Beaulieu, P.L.,Stammers, T. Enantiomeric Atropisomers Inhibit HCV Polymerase and/or HIV Matrix: Characterizing Hindered Bond Rotations and Target Selectivity. J.Med.Chem., 57:1944-1951, 2014 Cited by PubMed 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. PubMed: 24024973DOI: 10.1021/jm401202a PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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