3Q0Z

Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5h-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid

Summary for 3Q0Z

• Entry DOI: 10.2210/pdb3q0z/pdb
• Descriptor: RNA-directed RNA polymerase, (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: ns5b, polymerase, hcv, fingers, palm, thumb, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Hepatitis C virus subtype 1b
• 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): Q9WMX2
• Total number of polymer chains: 2
• Total formula weight: 130145.13

Authors

Sheriff, S. (deposition date: 2010-12-16, release date: 2011-04-27, Last modification date: 2023-09-13)

Primary citation

Zheng, X.,Hudyma, T.W.,Martin, S.W.,Bergstrom, C.,Ding, M.,He, F.,Romine, J.,Poss, M.A.,Kadow, J.F.,Chang, C.H.,Wan, J.,Witmer, M.R.,Morin, P.,Camac, D.M.,Sheriff, S.,Beno, B.R.,Rigat, K.L.,Wang, Y.K.,Fridell, R.,Lemm, J.,Qiu, D.,Liu, M.,Voss, S.,Pelosi, L.,Roberts, S.B.,Gao, M.,Knipe, J.,Gentles, R.G.
Syntheses and initial evaluation of a series of indolo-fused heterocyclic inhibitors of the polymerase enzyme (NS5B) of the hepatitis C virus.
Bioorg.Med.Chem.Lett., 21:2925-2929, 2011

PubMed Abstract: Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC(50)=0.07 μM, %F=18), are reported.

PubMed: 21486696
DOI: 10.1016/j.bmcl.2011.03.067

Experimental method

X-RAY DIFFRACTION (2.29 Å)