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- PDB-5lwp: Discovery of phenoxyindazoles and phenylthioindazoles as RORg inv... -

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Basic information

Entry
Database: PDB / ID: 5lwp
TitleDiscovery of phenoxyindazoles and phenylthioindazoles as RORg inverse agonists
ComponentsNuclear receptor ROR-gamma
KeywordsTRANSCRIPTION / ROR gamma allosteric ligand inverse agonistM
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-79U / Nuclear receptor ROR-gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.4 Å
AuthorsOuvry, G. / Bouix-Peter, C. / Ciesielski, F. / Chantalat, L. / Christin, O. / Comino, C. / Duvert, D. / Feret, C. / Harris, C.S. / Luzy, A.-P. ...Ouvry, G. / Bouix-Peter, C. / Ciesielski, F. / Chantalat, L. / Christin, O. / Comino, C. / Duvert, D. / Feret, C. / Harris, C.S. / Luzy, A.-P. / Musicki, B. / Orfila, D. / Pascau, J. / Parnet, V. / Perrin, A. / Pierre, R. / Raffin, C. / Rival, Y. / Taquet, N. / Thoreau, E. / Hennequin, L.F.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Discovery of phenoxyindazoles and phenylthioindazoles as ROR gamma inverse agonists.
Authors: Ouvry, G. / Bouix-Peter, C. / Ciesielski, F. / Chantalat, L. / Christin, O. / Comino, C. / Duvert, D. / Feret, C. / Harris, C.S. / Lamy, L. / Luzy, A.P. / Musicki, B. / Orfila, D. / Pascau, ...Authors: Ouvry, G. / Bouix-Peter, C. / Ciesielski, F. / Chantalat, L. / Christin, O. / Comino, C. / Duvert, D. / Feret, C. / Harris, C.S. / Lamy, L. / Luzy, A.P. / Musicki, B. / Orfila, D. / Pascau, J. / Parnet, V. / Perrin, A. / Pierre, R. / Polge, G. / Raffin, C. / Rival, Y. / Taquet, N. / Thoreau, E. / Hennequin, L.F.
History
DepositionSep 19, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 16, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 7, 2016Group: Database references
Revision 1.2Jan 17, 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)28,9942
Polymers28,4901
Non-polymers5041
Water79344
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)173.810, 173.810, 68.400
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number155
Space group name H-MH32

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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: 28490.084 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RORC, NR1F3, RORG, RZRG / Production host: Escherichia coli (E. coli) / References: UniProt: P51449
#2: Chemical ChemComp-79U / 4-[3-[2-chloranyl-6-(trifluoromethyl)phenoxy]-5-(dimethylcarbamoyl)indazol-1-yl]benzoic acid


Mass: 503.858 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H17ClF3N3O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 44 / 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: 3.49 Å3/Da / Density % sol: 64.75 %
Crystal growTemperature: 278 K / Method: vapor diffusion, sitting drop / Details: 0.1M Hepes pH8.5, 0.1M MgCl2, 7% PEG6000

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Data collection

DiffractionMean temperature: 278 K
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97857 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 16, 2014
Details: Kirkpatrick-Baez pair of bi-morph mirrors plus channel cut cryogenically cooled monochromator crystal
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2.4→29.313 Å / Num. obs: 15503 / % possible obs: 99.7 % / Observed criterion σ(I): -3 / Redundancy: 7.07 % / Biso Wilson estimate: 55.298 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.057 / Net I/av σ(I): 31.98 / Net I/σ(I): 21.98
Reflection shellResolution: 2.4→2.54 Å / Redundancy: 7.1 % / Rmerge(I) obs: 0.509 / Mean I/σ(I) obs: 3.98 / CC1/2: 0.923 / % possible all: 99.1

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 34.07 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.54 Å43.82 Å
Translation2.54 Å43.82 Å

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHASER2.1.4phasing
REFMAC5.8.0135refinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3B0W

3b0w


Resolution: 2.4→29.31 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.929 / SU B: 7.727 / SU ML: 0.179 / SU R Cruickshank DPI: 0.2761 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.276 / ESU R Free: 0.232 / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2533 776 5 %RANDOM
Rwork0.2001 ---
obs0.2028 14726 99.75 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 134.09 Å2 / Biso mean: 52.239 Å2 / Biso min: 19.69 Å2
Baniso -1Baniso -2Baniso -3
1--1.16 Å2-0.58 Å20 Å2
2---1.16 Å20 Å2
3---3.78 Å2
Refinement stepCycle: final / Resolution: 2.4→29.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1984 0 35 44 2063
Biso mean--43.64 48.97 -
Num. residues----244
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0192066
X-RAY DIFFRACTIONr_angle_refined_deg1.9921.9682791
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1685243
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.14623.1100
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.36615368
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.9151516
X-RAY DIFFRACTIONr_chiral_restr0.1390.2302
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211562
X-RAY DIFFRACTIONr_mcbond_it4.7364.899975
X-RAY DIFFRACTIONr_mcangle_it6.5287.3251217
X-RAY DIFFRACTIONr_scbond_it6.7165.521088
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.331 56 -
Rwork0.289 1054 -
all-1110 -
obs--98.06 %

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