2BRK
Crystal structure of Hepatitis C virus polymerase in complex with an allosteric inhibitor (compound 1)
Summary for 2BRK
| Entry DOI | 10.2210/pdb2brk/pdb |
| Related | 1A1Q 1C2P 1CSJ 1CU1 1GX5 1GX6 1JXP 1NS3 1QUV 2BRL 8OHM |
| Descriptor | RNA-DIRECTED RNA POLYMERASE, MANGANESE (II) ION, 3-CYCLOHEXYL-1-(2-MORPHOLIN-4-YL-2-OXOETHYL)-2-PHENYL-1H-INDOLE-6-CARBOXYLIC ACID, ... (4 entities in total) |
| Functional Keywords | transferase, hepatitis c virus, hcv, ns5b, polymerase, rna-dependent rna- polymerase, allosteric inhibitor, atp-binding |
| Biological source | HEPATITIS C VIRUS |
| Cellular location | Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein. 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): P26663 |
| Total number of polymer chains | 1 |
| Total formula weight | 60197.92 |
| Authors | Di Marco, S.,Volpari, C.,Carfi, A. (deposition date: 2005-05-06, release date: 2005-06-14, Last modification date: 2023-12-13) |
| Primary citation | Di Marco, S.,Volpari, C.,Tomei, L.,Altamura, S.,Harper, S.,Narjes, F.,Koch, U.,Rowley, M.,De Francesco, R.,Migliaccio, G.,Carfi, A. Interdomain Communication in Hepatitis C Virus Polymerase Abolished by Small-Molecule Inhibitors Bound to a Novel Allosteric Site J.Biol.Chem., 280:29765-, 2005 Cited by PubMed Abstract: The hepatitis C virus (HCV) polymerase is required for replication of the viral genome and is a key target for therapeutic intervention against HCV. We have determined the crystal structures of the HCV polymerase complexed with two indole-based allosteric inhibitors at 2.3- and 2.4-Angstroms resolution. The structures show that these inhibitors bind to a site on the surface of the thumb domain. A cyclohexyl and phenyl ring substituents, bridged by an indole moiety, fill two closely spaced pockets, whereas a carboxylate substituent forms a salt bridge with an exposed arginine side chain. Interestingly, in the apoenzyme, the inhibitor binding site is occupied by a small alpha-helix at the tip of the N-terminal loop that connects the fingers and thumb domains. Thus, these molecules inhibit the enzyme by preventing formation of intramolecular contacts between these two domains and consequently precluding their coordinated movements during RNA synthesis. Our structures identify a novel mechanism by which a new class of allosteric inhibitors inhibits the HCV polymerase and open the way to the development of novel antiviral agents against this clinically relevant human pathogen. PubMed: 15955819DOI: 10.1074/JBC.M505423200 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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