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- PDB-6vke: Crystal Structure of Inhibitor JNJ-40012665 in Complex with Prefu... -

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Basic information

Entry
Database: PDB / ID: 6vke
TitleCrystal Structure of Inhibitor JNJ-40012665 in Complex with Prefusion RSV F Glycoprotein
ComponentsPrefusion RSV F (DS-Cav1)
KeywordsVIRAL PROTEIN / Inhibitor / complex
Function / homology
Function and homology information


symbiont-mediated induction of syncytium formation / Translation of respiratory syncytial virus mRNAs / RSV-host interactions / Assembly and release of respiratory syncytial virus (RSV) virions / Maturation of hRSV A proteins / host cell Golgi membrane / Respiratory syncytial virus (RSV) attachment and entry / entry receptor-mediated virion attachment to host cell / symbiont entry into host cell / fusion of virus membrane with host plasma membrane ...symbiont-mediated induction of syncytium formation / Translation of respiratory syncytial virus mRNAs / RSV-host interactions / Assembly and release of respiratory syncytial virus (RSV) virions / Maturation of hRSV A proteins / host cell Golgi membrane / Respiratory syncytial virus (RSV) attachment and entry / entry receptor-mediated virion attachment to host cell / symbiont entry into host cell / fusion of virus membrane with host plasma membrane / viral envelope / host cell plasma membrane / virion membrane / identical protein binding / plasma membrane
Similarity search - Function
Precursor fusion glycoprotein F0, Paramyxoviridae / Fusion glycoprotein F0 / Fibritin C-terminal / Fibritin C-terminal region
Similarity search - Domain/homology
Chem-R0S / Envelope glycoprotein / Fusion glycoprotein F0 / Fusion glycoprotein F0
Similarity search - Component
Biological speciesHuman respiratory syncytial virus
Human immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsMcLellan, J.S.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of 3-({5-Chloro-1-[3-(methylsulfonyl)propyl]-1H-indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (JNJ-53718678), a Potent and Orally ...Title: Discovery of 3-({5-Chloro-1-[3-(methylsulfonyl)propyl]-1H-indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (JNJ-53718678), a Potent and Orally Bioavailable Fusion Inhibitor of Respiratory Syncytial Virus.
Authors: Vendeville, S. / Tahri, A. / Hu, L. / Demin, S. / Cooymans, L. / Vos, A. / Kwanten, L. / Van den Berg, J. / Battles, M.B. / McLellan, J.S. / Koul, A. / Raboisson, P. / Roymans, D. / Jonckers, T.H.M.
History
DepositionJan 20, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 27, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 1, 2020Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Aug 26, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
F: Prefusion RSV F (DS-Cav1)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,3839
Polymers63,2181
Non-polymers1,1648
Water5,999333
1
F: Prefusion RSV F (DS-Cav1)
hetero molecules

F: Prefusion RSV F (DS-Cav1)
hetero molecules

F: Prefusion RSV F (DS-Cav1)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)193,14827
Polymers189,6553
Non-polymers3,49324
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555z,x,y1
crystal symmetry operation9_555y,z,x1
Buried area18170 Å2
ΔGint-280 kcal/mol
Surface area47830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)168.770, 168.770, 168.770
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number213
Space group name H-MP4132
Components on special symmetry positions
IDModelComponents
11F-968-

HOH

21F-1001-

HOH

31F-1019-

HOH

41F-1028-

HOH

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Components

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Protein , 1 types, 1 molecules F

#1: Protein Prefusion RSV F (DS-Cav1)


Mass: 63218.344 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human respiratory syncytial virus, (gene. exp.) Human immunodeficiency virus 1
Production host: Homo sapiens (human)
References: UniProt: W8RJF9, UniProt: M1E1E4, UniProt: P03420*PLUS

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Non-polymers , 5 types, 341 molecules

#2: Chemical ChemComp-NHE / 2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID / N-CYCLOHEXYLTAURINE / CHES


Mass: 207.290 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H17NO3S / Comment: pH buffer*YM
#3: Chemical ChemComp-R0S / 4-(5-chloro-2-{[1-(3,4-dimethoxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl]methyl}-1H-indol-1-yl)butanenitrile


Mass: 501.964 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H24ClN5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 333 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.17 Å3/Da / Density % sol: 61.18 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 1.64M K/Na tartrate, 0.2M LiSO4, 0.1M CHES pH 9.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97926 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 20, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97926 Å / Relative weight: 1
ReflectionResolution: 2.1→45.11 Å / Num. obs: 48387 / % possible obs: 100 % / Redundancy: 19.5 % / Biso Wilson estimate: 32.67 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.186 / Rpim(I) all: 0.043 / Rrim(I) all: 0.191 / Net I/σ(I): 12 / Num. measured all: 945480 / Scaling rejects: 15
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.1-2.1615.41.6216017739070.6690.4171.6761.9100
8.91-45.1116.10.093121597530.9980.0230.09629.998.7

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Processing

Software
NameVersionClassification
Aimless0.5.27data scaling
PHENIX1.13_2998refinement
PDB_EXTRACT3.25data extraction
iMOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5EA4

5ea4


Resolution: 2.1→40.933 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 18.26
RfactorNum. reflection% reflection
Rfree0.1993 2409 4.99 %
Rwork0.1784 --
obs0.1795 48314 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 130.35 Å2 / Biso mean: 45.139 Å2 / Biso min: 9.34 Å2
Refinement stepCycle: final / Resolution: 2.1→40.933 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3343 0 71 333 3747
Biso mean--78.98 46.49 -
Num. residues----432
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
2.1003-2.14320.28361350.26392643
2.1432-2.18980.32291220.24572686
2.1898-2.24070.22621510.23022616
2.2407-2.29670.24361440.21812673
2.2967-2.35880.24061350.20982662
2.3588-2.42820.21891440.19472625
2.4282-2.50660.20761370.19492684
2.5066-2.59620.24251420.19582693
2.5962-2.70010.20251420.18532637
2.7001-2.82290.20281590.18772658
2.8229-2.97170.23531550.19032680
2.9717-3.15790.19921440.17862699
3.1579-3.40160.18761360.17432717
3.4016-3.74370.20461380.15272733
3.7437-4.28490.15831290.14242751
4.2849-5.39660.14941420.14052793
5.3966-40.9330.19881540.19772955
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.8905-0.457-0.1640.7366-0.54530.8011-0.01350.0011-0.250.0033-0.01410.190.316-0.1870.07590.1976-0.0284-0.0110.23670.0330.27173.7949-4.35219.9496
22.64762.38933.14313.85075.11657.4752-0.24160.5756-0.2511-0.56930.20540.114-0.31860.3009-0.13140.4808-0.03-0.03370.3482-0.0170.34668.8726-9.4263-5.4651
33.29761.4980.05792.85731.13741.7543-0.02230.4574-0.9586-0.21580.0787-0.07380.76220.1591-0.18620.7104-0.0017-0.02810.278-0.07640.63988.8348-25.9586-1.0416
41.6360.05970.53811.34640.9393.6056-0.05980.112-0.3942-0.0856-0.04910.25690.4398-0.28750.00850.3378-0.0671-0.05230.2279-0.03420.39692.5305-14.69635.3624
51.5018-0.128-0.34336.86591.51062.1008-0.0357-0.1124-0.0001-0.23050.01980.1042-0.0467-0.12850.04920.12780.0081-0.03250.24010.04070.14017.19849.201128.0155
61.8823-0.95070.44732.2544-0.05381.1123-0.038-0.27780.13790.23820.0011-0.0796-0.0926-0.07940.03240.27180.01050.01170.2806-0.00320.20084.909519.931332.3897
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'F' and (resid 27 through 73 )F27 - 73
2X-RAY DIFFRACTION2chain 'F' and (resid 74 through 148 )F74 - 148
3X-RAY DIFFRACTION3chain 'F' and (resid 149 through 216 )F149 - 216
4X-RAY DIFFRACTION4chain 'F' and (resid 217 through 309 )F217 - 309
5X-RAY DIFFRACTION5chain 'F' and (resid 310 through 371 )F310 - 371
6X-RAY DIFFRACTION6chain 'F' and (resid 372 through 506 )F372 - 506

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