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- PDB-6q6o: RORCVAR2 (RORGT, 264-499) IN COMPLEX WITH COMPOUND 2 AT 2.3A: Ide... -

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Basic information

Entry
Database: PDB / ID: 6q6o
TitleRORCVAR2 (RORGT, 264-499) IN COMPLEX WITH COMPOUND 2 AT 2.3A: 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
CHOLIC ACID / Chem-HKE / Nuclear receptor ROR-gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 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)28,8174
Polymers27,6301
Non-polymers1,1873
Water1,63991
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1350 Å2
ΔGint9 kcal/mol
Surface area11880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.103, 102.103, 128.425
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 / Plasmid: pET28-derived vector / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: P51449
#2: Chemical ChemComp-HKE / propan-2-yl (2~{S})-2-[[2,6-bis(chloranyl)phenyl]-(furan-2-ylcarbonyl)amino]propanoate


Mass: 370.227 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17Cl2NO4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CHD / CHOLIC ACID


Mass: 408.571 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H40O5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 91 / 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: 64.83 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.8
Details: 0.5% PEG MME 5k (w/v), 0.74M 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: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 27, 2010
RadiationMonochromator: SI 111 channel / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→19.64 Å / Num. obs: 18163 / % possible obs: 99.7 % / Redundancy: 18.6 % / Biso Wilson estimate: 46.1 Å2 / Rmerge(I) obs: 0.054 / Rpim(I) all: 0.026 / Rrim(I) all: 0.055 / Net I/σ(I): 41.9
Reflection shellResolution: 2.3→2.36 Å / Redundancy: 19.3 % / Rmerge(I) obs: 0.36 / Mean I/σ(I) obs: 11 / Rpim(I) all: 0.122 / Rrim(I) all: 0.37 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6Q6M

6q6m


Resolution: 2.3→19.64 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.931 / SU B: 5.097 / SU ML: 0.128 / SU R Cruickshank DPI: 0.2426 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.243 / ESU R Free: 0.195
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2431 909 5 %RANDOM
Rwork0.2205 ---
obs0.2217 17254 99.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 83.29 Å2 / Biso mean: 44.065 Å2 / Biso min: 25.63 Å2
Baniso -1Baniso -2Baniso -3
1-0.58 Å20.29 Å20 Å2
2--0.58 Å20 Å2
3----0.87 Å2
Refinement stepCycle: final / Resolution: 2.3→19.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1850 0 82 91 2023
Biso mean--66.71 44.77 -
Num. residues----226
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0211976
X-RAY DIFFRACTIONr_angle_refined_deg1.0321.9992674
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.1075225
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.02123.02196
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.84315354
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6361517
X-RAY DIFFRACTIONr_chiral_restr0.0680.2302
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.021445
LS refinement shellResolution: 2.3→2.359 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.384 65 -
Rwork0.257 1222 -
all-1287 -
obs--99.92 %

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