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- PDB-6p9f: Crystal structure of RAR-related orphan receptor C (NHIS-RORGT(24... -

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Basic information

Entry
Database: PDB / ID: 6p9f
TitleCrystal structure of RAR-related orphan receptor C (NHIS-RORGT(244-487)-L6-SRC1(678-692)) in complex with a phenyl (3-phenylpyrrolidin-3-yl)sulfone inhibitor
ComponentsNuclear receptor ROR-gamma, Nuclear receptor coactivator 1 chimera
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / RORGT / nuclear hormone receptor / ligand-binding domain / INVE agonist / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


cellular response to sterol / T-helper 17 cell differentiation / regulation of steroid metabolic process / ligand-modulated transcription factor activity / Peyer's patch development / T-helper cell differentiation / positive regulation of circadian rhythm / RUNX3 Regulates Immune Response and Cell Migration / oxysterol binding / labyrinthine layer morphogenesis ...cellular response to sterol / T-helper 17 cell differentiation / regulation of steroid metabolic process / ligand-modulated transcription factor activity / Peyer's patch development / T-helper cell differentiation / positive regulation of circadian rhythm / RUNX3 Regulates Immune Response and Cell Migration / oxysterol binding / labyrinthine layer morphogenesis / negative regulation of thymocyte apoptotic process / positive regulation of transcription from RNA polymerase II promoter by galactose / regulation of thyroid hormone receptor signaling pathway / positive regulation of female receptivity / regulation of fat cell differentiation / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / hypothalamus development / male mating behavior / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Endogenous sterols / adipose tissue development / lymph node development / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear retinoid X receptor binding / response to retinoic acid / progesterone receptor signaling pathway / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / cellular response to hormone stimulus / histone H4K16 acetyltransferase activity / histone H3K56 acetyltransferase activity / histone H3K23 acetyltransferase activity / histone H2AK5 acetyltransferase activity / histone H2AK9 acetyltransferase activity / histone H2BK5 acetyltransferase activity / histone H2BK12 acetyltransferase activity / histone H3K4 acetyltransferase activity / histone H3K27 acetyltransferase activity / histone H3K36 acetyltransferase activity / histone H3K122 acetyltransferase activity / histone H3K18 acetyltransferase activity / histone H3K9 acetyltransferase activity / histone H3K14 acetyltransferase activity / histone H4K5 acetyltransferase activity / histone H4K8 acetyltransferase activity / histone H4K12 acetyltransferase activity / Recycling of bile acids and salts / histone acetyltransferase / estrous cycle / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / estrogen receptor signaling pathway / positive regulation of adipose tissue development / : / lactation / Regulation of lipid metabolism by PPARalpha / peroxisome proliferator activated receptor signaling pathway / regulation of cellular response to insulin stimulus / xenobiotic metabolic process / positive regulation of neuron differentiation / cerebellum development / BMAL1:CLOCK,NPAS2 activates circadian expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / hippocampus development / response to progesterone / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / nuclear estrogen receptor binding / circadian regulation of gene expression / mRNA transcription by RNA polymerase II / Heme signaling / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / cerebral cortex development / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / DNA-binding transcription repressor activity, RNA polymerase II-specific / RNA polymerase II transcription regulator complex / nuclear receptor activity / male gonad development / sequence-specific double-stranded DNA binding / : / response to estradiol / HATs acetylate histones / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / Interleukin-4 and Interleukin-13 signaling / transcription regulator complex / Estrogen-dependent gene expression / transcription coactivator activity / DNA-binding transcription factor activity, RNA polymerase II-specific / protein dimerization activity / nuclear body / positive regulation of apoptotic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / chromatin binding / regulation of transcription by RNA polymerase II
Similarity search - Function
Nuclear receptor ROR / Retinoid-related orphan receptors, DNA-binding domain / Nuclear receptor coactivator 1 / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain ...Nuclear receptor ROR / Retinoid-related orphan receptors, DNA-binding domain / Nuclear receptor coactivator 1 / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain / Nuclear receptor coactivator / : / Steroid receptor coactivator / Unstructured region on nuclear receptor coactivator protein / Nuclear receptor coactivators bHLH domain / PAS domain / Nuclear receptor coactivator, interlocking / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Helix-loop-helix DNA-binding domain superfamily / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / Retinoid X Receptor / Retinoid X Receptor / PAS domain superfamily / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Double treble clef zinc finger, C4 type / 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-O5A / Nuclear receptor ROR-gamma / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsSack, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: Identification of potent, selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as ROR gamma t inverse agonists.
Authors: Lu, Z. / Duan, J.J. / Xiao, H. / Neels, J. / Wu, D.R. / Weigelt, C.A. / Sack, J.S. / Khan, J. / Ruzanov, M. / An, Y. / Yarde, M. / Karmakar, A. / Vishwakrishnan, S. / Baratam, V. / ...Authors: Lu, Z. / Duan, J.J. / Xiao, H. / Neels, J. / Wu, D.R. / Weigelt, C.A. / Sack, J.S. / Khan, J. / Ruzanov, M. / An, Y. / Yarde, M. / Karmakar, A. / Vishwakrishnan, S. / Baratam, V. / Shankarappa, H. / Vanteru, S. / Babu, V. / Basha, M. / Kumar Gupta, A. / Kumaravel, S. / Mathur, A. / Zhao, Q. / Salter-Cid, L.M. / Carter, P.H. / Murali Dhar, T.G.
History
DepositionJun 10, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 17, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 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

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Assembly

Deposited unit
A: Nuclear receptor ROR-gamma, Nuclear receptor coactivator 1 chimera
B: Nuclear receptor ROR-gamma, Nuclear receptor coactivator 1 chimera
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,0294
Polymers65,7742
Non-polymers1,2552
Water41423
1
A: Nuclear receptor ROR-gamma, Nuclear receptor coactivator 1 chimera
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,5142
Polymers32,8871
Non-polymers6281
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Nuclear receptor ROR-gamma, Nuclear receptor coactivator 1 chimera
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,5142
Polymers32,8871
Non-polymers6281
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)64.128, 64.128, 159.666
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number76
Space group name H-MP41

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Components

#1: Protein Nuclear receptor ROR-gamma, Nuclear receptor coactivator 1 chimera / 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 / NCoA-1 / Class E basic helix-loop-helix protein 74 / bHLHe74 / Protein Hin-2 / RIP160 / Renal carcinoma antigen NY-REN-52 / Steroid receptor coactivator 1 / SRC-1


Mass: 32886.922 Da / Num. of mol.: 2
Fragment: ligand-binding domain (UNP residues 265-508) fused to SRC peptide (UNP residues 683-696)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RORC, NR1F3, RORG, RZRG, NCOA1, BHLHE74, SRC1 / Production host: Escherichia coli (E. coli)
References: UniProt: P51449, UniProt: Q15788, histone acetyltransferase
#2: Chemical ChemComp-O5A / trans-4-{(3R)-3-[(4-fluorophenyl)sulfonyl]-3-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl]pyrrolidine-1-carbonyl}cyclohexane-1-carboxylic acid


Mass: 627.543 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C27H25F8NO5S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 23 / Source method: isolated from a natural source / Formula: H2O
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: 2.5 Å3/Da / Density % sol: 50.72 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 20-26% PEG3350, 0.2 M magnesium chloride, 0.1 M Bis-Tris pH 5.5-6.5
PH range: 5.5-6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.98 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: May 21, 2015
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.8→159.67 Å / Num. obs: 15848 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 6.4 % / Biso Wilson estimate: 87.62 Å2 / Rmerge(I) obs: 0.045 / Net I/σ(I): 24.4
Reflection shellResolution: 2.8→2.95 Å / Redundancy: 6.4 % / Rmerge(I) obs: 0.37 / Mean I/σ(I) obs: 5 / Num. unique obs: 2302 / % possible all: 100

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTER2.11.7refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 6O98

6o98


Resolution: 2.8→64.13 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.93 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.31
RfactorNum. reflection% reflectionSelection details
Rfree0.223 836 5.29 %RANDOM
Rwork0.184 ---
obs0.186 15806 99.9 %-
Displacement parametersBiso mean: 72.79 Å2
Baniso -1Baniso -2Baniso -3
1--2.2422 Å20 Å20 Å2
2---2.2422 Å20 Å2
3---4.4843 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: LAST / Resolution: 2.8→64.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4181 0 84 23 4288
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014358HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.075895HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1571SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes761HARMONIC5
X-RAY DIFFRACTIONt_it4358HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.6
X-RAY DIFFRACTIONt_other_torsion18.91
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion539SEMIHARMONIC5
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_contact5004SEMIHARMONIC4
LS refinement shellResolution: 2.8→2.83 Å / Total num. of bins used: 41
RfactorNum. reflection% reflection
Rfree0.2562 -4.66 %
Rwork0.2278 368 -
all0.2289 386 -
obs--98.5 %

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