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- PDB-6q6m: RORCVAR2 (RORGT, 264-499) IN COMPLEX WITH COMPOUND 1: Identificat... -

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Basic information

Entry
Database: PDB / ID: 6q6m
TitleRORCVAR2 (RORGT, 264-499) IN COMPLEX WITH COMPOUND 1: Identification of N-aryl imidazoles as potent and selective RORgt inhibitors
ComponentsNuclear receptor ROR-gamma
KeywordsTRANSCRIPTION / nuclear hormone receptor / ligand-binding domain / inverse agonist
Function / homology
Function and homology information


cellular response to sterol / T-helper 17 cell differentiation / ligand-activated transcription factor activity / regulation of steroid metabolic process / Peyer's patch development / positive regulation of circadian rhythm / T-helper cell differentiation / RUNX3 Regulates Immune Response and Cell Migration / oxysterol binding / negative regulation of thymocyte apoptotic process ...cellular response to sterol / T-helper 17 cell differentiation / ligand-activated transcription factor activity / regulation of steroid metabolic process / Peyer's patch development / positive regulation of circadian rhythm / T-helper cell differentiation / RUNX3 Regulates Immune Response and Cell Migration / oxysterol binding / negative regulation of thymocyte apoptotic process / regulation of fat cell differentiation / regulation of glucose metabolic process / lymph node development / adipose tissue development / xenobiotic metabolic process / circadian regulation of gene expression / DNA-binding transcription repressor activity, RNA polymerase II-specific / Nuclear Receptor transcription pathway / nuclear receptor activity / sequence-specific double-stranded DNA binding / Interleukin-4 and Interleukin-13 signaling / nuclear body / DNA-binding transcription factor activity, RNA polymerase II-specific / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / chromatin / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
Nuclear receptor ROR / Retinoid-related orphan receptors, DNA-binding domain / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors ...Nuclear receptor ROR / Retinoid-related orphan receptors, DNA-binding domain / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors / Nuclear hormone receptor, ligand-binding domain / Nuclear hormone receptor-like domain superfamily / Ligand-binding domain of nuclear hormone receptor / Nuclear receptor (NR) ligand-binding (LBD) domain profile. / Ligand binding domain of hormone receptors / Zinc finger, NHR/GATA-type / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-HJW / Nuclear receptor ROR-gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.35 Å
AuthorsKallen, J.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Structure-Based and Property-Driven Optimization ofN-Aryl Imidazoles toward Potent and Selective Oral ROR gamma t Inhibitors.
Authors: Hoegenauer, K. / Kallen, J. / Jimenez-Nunez, E. / Strang, R. / Ertl, P. / Cooke, N.G. / Hintermann, S. / Voegtle, M. / Betschart, C. / McKay, D.J.J. / Wagner, J. / Ottl, J. / Beerli, C. / ...Authors: Hoegenauer, K. / Kallen, J. / Jimenez-Nunez, E. / Strang, R. / Ertl, P. / Cooke, N.G. / Hintermann, S. / Voegtle, M. / Betschart, C. / McKay, D.J.J. / Wagner, J. / Ottl, J. / Beerli, C. / Billich, A. / Dawson, J. / Kaupmann, K. / Streiff, M. / Gobeau, N. / Harlfinger, S. / Stringer, R. / Guntermann, C.
History
DepositionDec 11, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 27, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2019Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Jan 24, 2024Group: 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

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Assembly

Deposited unit
A: Nuclear receptor ROR-gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,9822
Polymers27,6301
Non-polymers3521
Water1,02757
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area11960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.015, 102.015, 128.860
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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Components

#1: Protein Nuclear receptor ROR-gamma / Nuclear receptor RZR-gamma / Nuclear receptor subfamily 1 group F member 3 / RAR-related orphan ...Nuclear receptor RZR-gamma / Nuclear receptor subfamily 1 group F member 3 / RAR-related orphan receptor C / Retinoid-related orphan receptor-gamma


Mass: 27629.943 Da / Num. of mol.: 1 / Fragment: C-terminal domain, ligand binding domain / Mutation: C455S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RORC, NR1F3, RORG, RZRG / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: P51449
#2: Chemical ChemComp-HJW / ethyl (2~{S})-2-[(2-chloranyl-6-methyl-phenyl)-thiophen-2-ylcarbonyl-amino]propanoate


Mass: 351.848 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H18ClNO3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 57 / Source method: isolated from a natural source / Formula: H2O

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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: 3.5 Å3/Da / Density % sol: 64.89 % / Mosaicity: 0.484 °
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.2
Details: 0.5% PEG MME 5k (w/v), 0.6 M KNa Tartrate 0.1M TRIS

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9794 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 7, 2008
RadiationMonochromator: SI 111 channel / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9794 Å / Relative weight: 1
ReflectionResolution: 2.35→20 Å / Num. obs: 17081 / % possible obs: 99.9 % / Redundancy: 13.7 % / Rmerge(I) obs: 0.068 / Χ2: 1.065 / Net I/σ(I): 45.26
Reflection shellResolution: 2.35→2.43 Å / Redundancy: 14.2 % / Rmerge(I) obs: 0.327 / Mean I/σ(I) obs: 5.43 / Num. unique obs: 1859 / Χ2: 2.091 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5NTI

5nti


Resolution: 2.35→20 Å / Cor.coef. Fo:Fc: 0.914 / Cor.coef. Fo:Fc free: 0.91 / SU B: 6.725 / SU ML: 0.163 / SU R Cruickshank DPI: 0.2828 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.283 / ESU R Free: 0.224
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2708 862 5.1 %RANDOM
Rwork0.2473 ---
obs0.2485 16169 99.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 79.74 Å2 / Biso mean: 48.133 Å2 / Biso min: 22.99 Å2
Baniso -1Baniso -2Baniso -3
1-0.47 Å20.23 Å20 Å2
2--0.47 Å20 Å2
3----0.7 Å2
Refinement stepCycle: final / Resolution: 2.35→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1850 0 23 57 1930
Biso mean--39.42 47.33 -
Num. residues----226
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0211911
X-RAY DIFFRACTIONr_angle_refined_deg1.1621.9592570
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.5825225
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.04423.02196
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.4515354
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4031517
X-RAY DIFFRACTIONr_chiral_restr0.0710.2279
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021437
LS refinement shellResolution: 2.35→2.41 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.307 73 -
Rwork0.268 1139 -
all-1212 -
obs--99.92 %

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