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- PDB-5c4u: Identification of a Novel Allosteric Binding Site for RORgt Inhibitors -

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Basic information

Entry
Database: PDB / ID: 5c4u
TitleIdentification of a Novel Allosteric Binding Site for RORgt Inhibitors
ComponentsNuclear receptor ROR-gamma
KeywordsTRANSCRIPTION/TRANSCRIPTION INHIBITOR / allosteric / inhibitor / TRANSCRIPTION-TRANSCRIPTION INHIBITOR complex
Function / homology
Function and homology information


T-helper 17 cell differentiation / ligand-activated transcription factor activity / cellular response to sterol / regulation of steroid metabolic process / Peyer's patch development / T-helper cell differentiation / positive regulation of circadian rhythm / oxysterol binding / RUNX3 Regulates Immune Response and Cell Migration / negative regulation of thymocyte apoptotic process ...T-helper 17 cell differentiation / ligand-activated transcription factor activity / cellular response to sterol / regulation of steroid metabolic process / Peyer's patch development / T-helper cell differentiation / positive regulation of circadian rhythm / oxysterol binding / RUNX3 Regulates Immune Response and Cell Migration / 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 / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / 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-4Y7 / Nuclear receptor ROR-gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.08 Å
AuthorsParthasarathy, G. / Soisson, S.
CitationJournal: Nat Commun / Year: 2015
Title: Identification of an allosteric binding site for ROR gamma t inhibition.
Authors: Scheepstra, M. / Leysen, S. / van Almen, G.C. / Miller, J.R. / Piesvaux, J. / Kutilek, V. / van Eenennaam, H. / Zhang, H. / Barr, K. / Nagpal, S. / Soisson, S.M. / Kornienko, M. / Wiley, K. ...Authors: Scheepstra, M. / Leysen, S. / van Almen, G.C. / Miller, J.R. / Piesvaux, J. / Kutilek, V. / van Eenennaam, H. / Zhang, H. / Barr, K. / Nagpal, S. / Soisson, S.M. / Kornienko, M. / Wiley, K. / Elsen, N. / Sharma, S. / Correll, C.C. / Trotter, B.W. / van der Stelt, M. / Oubrie, A. / Ottmann, C. / Parthasarathy, G. / Brunsveld, L.
History
DepositionJun 18, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 16, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)28,9415
Polymers28,1851
Non-polymers7564
Water41423
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)108.080, 108.080, 106.550
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: 28184.672 Da / Num. of mol.: 1 / Fragment: Ligand-binding residues 267-507
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-4Y7 / 4-{1-[2-chloro-6-(trifluoromethyl)benzoyl]-1H-pyrazolo[4,3-b]pyridin-3-yl}-5-fluoro-2-hydroxybenzoic acid


Mass: 479.768 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H10ClF4N3O4
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 23 / 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: 3.19 Å3/Da / Density % sol: 61.4 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 1.2 to 1.8M Ammonium sulfate, 0.1 M Tris HCl / PH range: 8 - 9

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Data collection

DiffractionMean temperature: 273 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Mar 10, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.08→46.8 Å / Num. obs: 18267 / % possible obs: 99.54 % / Redundancy: 19.2 % / Biso Wilson estimate: 54.54 Å2 / Net I/σ(I): 5.39

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
Aimlessdata scaling
PDB_EXTRACT3.15data extraction
XDSdata reduction
PHASERphasing
RefinementResolution: 2.08→37.94 Å / Cor.coef. Fo:Fc: 0.9457 / Cor.coef. Fo:Fc free: 0.9197 / SU R Cruickshank DPI: 0.184 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.184 / SU Rfree Blow DPI: 0.174 / SU Rfree Cruickshank DPI: 0.175
RfactorNum. reflection% reflectionSelection details
Rfree0.2771 1146 5.08 %RANDOM
Rwork0.2306 ---
obs0.2331 22579 99.78 %-
Displacement parametersBiso max: 144.1 Å2 / Biso mean: 59.82 Å2 / Biso min: 21.63 Å2
Baniso -1Baniso -2Baniso -3
1-5.2091 Å20 Å20 Å2
2--5.2091 Å20 Å2
3----10.4181 Å2
Refine analyzeLuzzati coordinate error obs: 0.366 Å
Refinement stepCycle: final / Resolution: 2.08→37.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1979 0 51 23 2053
Biso mean--59.69 57.83 -
Num. residues----241
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d766SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes49HARMONIC8
X-RAY DIFFRACTIONt_gen_planes344HARMONIC8
X-RAY DIFFRACTIONt_it2128HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion254SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2467SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2128HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2876HARMONIC21.11
X-RAY DIFFRACTIONt_omega_torsion1.93
X-RAY DIFFRACTIONt_other_torsion20.12
LS refinement shellResolution: 2.08→2.18 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.3086 136 4.67 %
Rwork0.2765 2775 -
all0.2779 2911 -
obs--99.78 %

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