5TWN

CRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS NS5B RNA- DEPENDENT RNA POLYMERASE IN COMPLEX WITH 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide

> Summary

Summary for 5TWN

Related5TWM
DescriptorNS5B RNA- DEPENDENT RNA POLYMERASE (E.C.2.7.7.48)
Functional Keywordsns5b, polymerase, hcv, fingers, palm, thumb, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
Biological sourceHepatitis C virus genotype 1b (isolate Con1) (HCV)
Cellular locationCore protein p21: Host endoplasmic reticulum membrane ; Single-pass membrane protein . Core protein p19: Virion . Envelope glycoprotein E1: Virion membrane ; Single-pass type I membrane protein . Envelope glycoprotein E2: Virion membrane ; Single-pass type I membrane protein . p7: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Protease NS2-3: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Serine protease NS3: Host endoplasmic reticulum membrane ; Peripheral membrane protein . Non-structural protein 4A: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein . Non-structural protein 4B: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Non-structural protein 5A: Host endoplasmic reticulum membrane ; Peripheral membrane protein . RNA-directed RNA polymerase: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein  Q9WMX2
Total number of polymer chains2
Total molecular weight130825.81
Authors
Sheriff, S. (deposition date: 2016-11-14, release date: 2017-03-15, Last modification date: 2017-04-26)
Primary citation
Eastman, K.J.,Parcella, K.,Yeung, K.-S.,Grant-Young, K.,Zhu, J.,Wang, T.,Zhang, Z.,Yin, Z.,Beno, B.R.,Sheriff, S.,Kish, K.,Tredup, J.,Jardel, A.G.,Szapiel, N.,Halan, V.,Ghosh, K.,Parker, D.,Mosure, K.,Fang, H.,Wang, Y.-K.,Lemm, J.,Zhuo, X.,Hanumegowda, U.,Liu, M.,Rigat, K.,Donoso, M.,Tuttle, M.,Zvyaga, T.,Haarhoff, Z.,Meanwell, N.A.,Soars, M.,Roberts, S.B.,Kadow, J.F.
The Discovery of a Pan-Genotypic, Primer Grip Inhibitor of HCV NS5B Polymerase
Medchemcomm, 8:796-, 2017
DOI: 10.1039/C6MD00636A
MImport into Mendeley
Experimental method
X-RAY DIFFRACTION (3.04 Å)
?

Structure validation

RfreeClashscoreRamachandran outliersSidechain outliersRSRZ outliers0.22730.7%4.3%4.8%MetricValuePercentile RanksWorseBetterPercentile relative to all X-ray structuresPercentile relative to X-ray structures of similar resolution

More Asymmetric unit images

Molmil generated image of 5twn
no rotation
Molmil generated image of 5twn
rotated about x axis by 90°
Molmil generated image of 5twn
rotated about y axis by 90°

More Biological unit images

Molmil generated image of 5twn
no rotation
Molmil generated image of 5twn
rotated about x axis by 90°
Molmil generated image of 5twn
rotated about y axis by 90°
(*)In the case of coarse surface representation, the asymmetric unit is shown as red ribbon representation.
Coordinate files for Biological unit (5twn.pdb1.gz [91.86 KB])
Coordinate files for Biological unit (5twn.pdb2.gz [90.84 KB])

> Structural details

Entity

Chain IDDescriptionTypeChain lengthFormula weightNumber of moleculesDB Name (Accession)Biological sourceDescriptive keywords
A, BNS5B RNA- DEPENDENT RNA POLYMERASEpolymer57463961.52
UniProt (Q9WMX2)
Pfam (PF00998)
Hepatitis C virus genotype 1b (isolate Con1) (HCV)
(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 acidnon-polymer630.72
SULFATE IONnon-polymer96.112
5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamidenon-polymer488.61

Sequence viewer

Contents of the asymmetric unit

PolymersNumber of chains2
Total molecular weight127923.0
Non-Polymers*Number of molecules15
Total molecular weight2902.8
All*Total molecular weight130825.8
*Water molecules are not included.

> Experimental details

Refinement Statistics

Experimental method:X-RAY DIFFRACTION (3.04 Å)

Cell axes66.00091.100233.300
Cell angles90.0090.0090.00
SpacegroupP 21 21 21
Resolution limits49.12 - 3.04
the highest resolution shell value3.150 - 3.040
R-factor0.19
R-work0.18900
the highest resolution shell value0.214
R-free0.22300
the highest resolution shell value0.270
RMSD bond length0.010
RMSD bond angle1.110

Data Collection Statistics

Resolution limits50.00 - 3.03
the highest resolution shell value -
Number of reflections27952
Completeness100.0
Redundancy6
the highest resolution shell value6.2
I/sigma(I)0

Crystallization Conditions

crystal IDmethodpHpH rangetemperatureunit
1VAPOR DIFFUSION, HANGING DROP5.6293

Crystallization Reagents

IDcrystal IDsolution IDreagent nameconcentrationdetails
Crystallization Reagents in Literatures*
IDcrystal IDsolutionreagent nameconcentration (unit)details
Annotated Information is extracted from Literature Info*

> Functional details

?

Functional Information from GO Data

ChainGOidnamespacecontents
?

Functional Information from PDB Data

site_idNumber of ResiduesDetails
AC111binding site for residue 23E A 601
ChainResidue
AALA395
AALA396
ALEU492
AGLY493
AVAL494
APRO495
APRO496
AARG498
AVAL499
AARG503
B23E601

AC23binding site for residue SO4 A 602
ChainResidue
ASER84
AVAL85
AARG120

AC35binding site for residue SO4 A 603
ChainResidue
AARG48
ALYS51
AARG158
ATHR221
ACYS223

AC44binding site for residue SO4 A 604
ChainResidue
AHIS374
ASER476
AARG517
AMET573

AC54binding site for residue SO4 A 605
ChainResidue
APRO496
ALEU497
AARG498
AARG570

AC63binding site for residue SO4 A 606
ChainResidue
AGLU361
ASER371
ASER478

AC74binding site for residue SO4 A 607
ChainResidue
ALYS79
AASP244
BLEU60
BLEU68

AC817binding site for residue 23E B 601
ChainResidue
ATHR399
AALA400
AHIS428
A23E601
BLEU392
BALA395
BALA396
BILE424
BHIS428
BLEU492
BGLY493
BVAL494
BPRO495
BPRO496
BARG498
BVAL499
BARG503

AC915binding site for residue 7NG B 602
ChainResidue
BARG200
BLEU204
BLEU314
BCYS316
BASP319
BVAL321
BILE363
BSER365
BCYS366
BSER368
BLEU384
BMET414
BTYR415
BTYR452
BPHE551

AD14binding site for residue SO4 B 603
ChainResidue
BSER84
BVAL85
BGLU86
BARG120

AD22binding site for residue SO4 B 604
ChainResidue
BGLY516
BARG517

AD33binding site for residue SO4 B 605
ChainResidue
ASER1
BLYS379
BARG380

AD42binding site for residue SO4 B 606
ChainResidue
BHIS475
BSER476

AD53binding site for residue SO4 B 607
ChainResidue
BARG48
BLYS51
BCYS223

AD63binding site for residue SO4 B 608
ChainResidue
BMET187
BGLY188
BSER189

?

Functional Information from PDB atom coordinates for the "HETATM" binding sites

site_idNumber of ResiduesDetails
23E_5twn_A_60120(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 binding site
ChainResidueligand
ATHR38923E: (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
APRO391-ALA39323E: (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
AALA395-ALA39623E: (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
ATHR39923E: (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
AILE424-LEU42523E: (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
AHIS428-PHE42923E: (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
ALEU492-PRO49623E: (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
AARG498-TRP50023E: (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
AARG50323E: (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

7NG_5twn_B_602325-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide binding site
ChainResidueligand
BPHE1937NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BTYR195-PRO1977NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BARG2007NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BLEU2047NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BLEU314-CYS3167NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BASP319-VAL3217NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BILE3237NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BLEU3607NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BILE363-CYS3667NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BSER368-VAL3707NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BLEU3847NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BILE413-TYR4157NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BILE447-TYR4487NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BTYR4527NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BLEU4667NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BTRP550-PHE5517NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide
BTYR5557NG: 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide

23E_5twn_B_60119(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 binding site
ChainResidueligand
BTHR38923E: (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
BLEU392-ALA39323E: (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
BALA395-ALA39623E: (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
BTHR39923E: (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
BILE424-LEU42523E: (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
BHIS428-PHE42923E: (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
BLEU492-PRO49623E: (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
BARG498-TRP50023E: (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
BARG50323E: (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

?

Functional Information from PROSITE/UniProt

site_idNumber of ResiduesDetails
?

Functional Information from SwissProt/UniProt

site_idNumber of ResiduesDetails
SWS_FT_FI13Charge relay system; for serine protease NS3 activity. {ECO:0000255|PROSITE- ProRule:PRU01166}.
ChainResidueDetails
ANA*
ANA*
ANA*

SWS_FT_FI23For protease NS2-3 activity; shared with dimeric partner. {ECO:0000255|PROSITE- ProRule:PRU01030}.
ChainResidueDetails
ANA*
ANA*
ANA*

SWS_FT_FI91ATP. {ECO:0000255|PROSITE- ProRule:PRU00541}.
ChainResidueDetails
ANA*

SWS_FT_FI123Charge relay system; for serine protease NS3 activity. {ECO:0000255|PROSITE- ProRule:PRU01166}.
ChainResidueDetails
BNA*
BNA*
BNA*

SWS_FT_FI133For protease NS2-3 activity; shared with dimeric partner. {ECO:0000255|PROSITE- ProRule:PRU01030}.
ChainResidueDetails
BNA*
BNA*
BNA*

SWS_FT_FI201ATP. {ECO:0000255|PROSITE- ProRule:PRU00541}.
ChainResidueDetails
BNA*

?

Catalytic Information from CSA

site_idNumber of ResiduesDetails

> Sequence Neighbor

> Downloads

Resources

PDBj@FacebookPDBj@TwitterwwPDBwwPDB FoundationEM DataBank

Copyright © 2013-2017 Protein Data Bank Japan