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- PDB-6e3g: Structure of RORgt in complex with a novel agonist. -

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Basic information

Entry
Database: PDB / ID: 6e3g
TitleStructure of RORgt in complex with a novel agonist.
Components
  • Nuclear receptor ROR-gamma
  • co-activator peptide
Keywordsnuclear protein/agonist / Nuclear hormone receptor / agonist / NUCLEAR PROTEIN / nuclear protein-agonist 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 / labyrinthine layer morphogenesis ...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 / labyrinthine layer morphogenesis / regulation of thyroid hormone mediated signaling pathway / negative regulation of thymocyte apoptotic process / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of female receptivity / regulation of fat cell differentiation / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / estrous cycle / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / lymph node development / Endogenous sterols / adipose tissue development / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear retinoid X receptor binding / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / response to retinoic acid / histone acetyltransferase activity / Recycling of bile acids and salts / regulation of cellular response to insulin stimulus / histone acetyltransferase / cellular response to hormone stimulus / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / positive regulation of neuron differentiation / RORA activates gene expression / lactation / Regulation of lipid metabolism by PPARalpha / xenobiotic metabolic process / cerebellum development / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / Activation of gene expression by SREBF (SREBP) / response to progesterone / nuclear estrogen receptor binding / nuclear receptor binding / hippocampus development / RNA polymerase II transcription regulatory region sequence-specific DNA binding / circadian regulation of gene expression / Heme signaling / mRNA transcription by RNA polymerase II / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / cerebral cortex development / DNA-binding transcription repressor activity, RNA polymerase II-specific / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / male gonad development / nuclear receptor activity / Circadian Clock / sequence-specific double-stranded DNA binding / response to estradiol / HATs acetylate histones / Interleukin-4 and Interleukin-13 signaling / Estrogen-dependent gene expression / transcription regulator complex / transcription coactivator activity / protein dimerization activity / nuclear body / DNA-binding transcription factor activity, RNA polymerase II-specific / positive regulation of apoptotic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / chromatin binding / chromatin / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / nucleoplasm / nucleus / plasma membrane / cytosol
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 / PAS domain / Nuclear receptor coactivator, interlocking / Helix-loop-helix DNA-binding domain superfamily / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily / 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-HOJ / Nuclear receptor ROR-gamma / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.1 Å
AuthorsSkene, R.J. / Hoffman, I.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Design, Synthesis, and Biological Evaluation of Retinoic Acid-Related Orphan Receptor gamma t (ROR gamma t) Agonist Structure-Based Functionality Switching Approach from In House ROR gamma t ...Title: Design, Synthesis, and Biological Evaluation of Retinoic Acid-Related Orphan Receptor gamma t (ROR gamma t) Agonist Structure-Based Functionality Switching Approach from In House ROR gamma t Inverse Agonist to ROR gamma t Agonist.
Authors: Yukawa, T. / Nara, Y. / Kono, M. / Sato, A. / Oda, T. / Takagi, T. / Sato, T. / Banno, Y. / Taya, N. / Imada, T. / Shiokawa, Z. / Negoro, N. / Kawamoto, T. / Koyama, R. / Uchiyama, N. / ...Authors: Yukawa, T. / Nara, Y. / Kono, M. / Sato, A. / Oda, T. / Takagi, T. / Sato, T. / Banno, Y. / Taya, N. / Imada, T. / Shiokawa, Z. / Negoro, N. / Kawamoto, T. / Koyama, R. / Uchiyama, N. / Skene, R. / Hoffman, I. / Chen, C.H. / Sang, B. / Snell, G. / Katsuyama, R. / Yamamoto, S. / Shirai, J.
History
DepositionJul 13, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 12, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Nuclear receptor ROR-gamma
C: co-activator peptide
B: Nuclear receptor ROR-gamma
D: co-activator peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,2308
Polymers59,1834
Non-polymers1,0474
Water6,612367
1
A: Nuclear receptor ROR-gamma
C: co-activator peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,1154
Polymers29,5912
Non-polymers5242
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1020 Å2
ΔGint-6 kcal/mol
Surface area12690 Å2
MethodPISA
2
B: Nuclear receptor ROR-gamma
D: co-activator peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,1154
Polymers29,5912
Non-polymers5242
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1060 Å2
ΔGint-7 kcal/mol
Surface area12620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.951, 61.951, 155.559
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number76
Space group name H-MP41

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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: 28568.107 Da / Num. of mol.: 2
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: Protein/peptide co-activator peptide


Mass: 1023.296 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: synthetic construct (others) / References: UniProt: Q15788*PLUS
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-HOJ / (5R)-6-acetyl-2-methoxy-N-{4-[(2-methoxyphenyl)methoxy]phenyl}-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide


Mass: 461.510 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C26H27N3O5
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 367 / 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: 2.52 Å3/Da / Density % sol: 51.23 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: 20% PEG3350, 0.2M AmmNitrate, 0.1M Citrate pH 6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.97 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 9, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.1→61.95 Å / Num. obs: 34222 / % possible obs: 100 % / Redundancy: 5 % / Rmerge(I) obs: 0.136 / Rpim(I) all: 0.071 / Rrim(I) all: 0.152 / Χ2: 1.01 / Net I/σ(I): 5.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Num. unique obsCC1/2Rpim(I) allΧ2% possible allRmerge(I) obsRrim(I) all
2.1-2.144.817360.5240.5480.952100
2.14-2.18516790.6530.4260.9391000.850.952
2.18-2.22517190.7640.3560.9741000.7130.798
2.22-2.26516830.7710.3291.28899.80.6550.734
2.26-2.31517310.80.3341.0481000.6740.753
2.31-2.375.116910.8680.2370.9811000.4780.534
2.37-2.425.117020.9040.2030.981000.4080.457
2.42-2.49517040.9020.1950.9971000.3930.439
2.49-2.565.117010.9180.1821.0061000.3680.411
2.56-2.655.117130.9380.1471.0061000.2960.331
2.65-2.74517090.9490.141.0231000.2810.314
2.74-2.855.117030.9790.1090.9881000.2190.245
2.85-2.98516990.9780.0880.9791000.1770.198
2.98-3.145.117110.9860.0721.0031000.1450.162
3.14-3.33517080.990.0560.9921000.1140.127
3.33-3.59517140.990.0511.0231000.1010.114
3.59-3.954.917190.9910.0451.0481000.0880.099
3.95-4.524.917240.9950.0341.0141000.0680.076
4.52-5.74.917250.9980.0240.9681000.0480.054
5.7-505.117510.9990.0170.99199.80.0350.039

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Processing

Software
NameVersionClassification
REFMACrefinement
HKL-2000data scaling
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
MOLREPphasing
RefinementResolution: 2.1→61.95 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.916 / WRfactor Rfree: 0.2258 / WRfactor Rwork: 0.1778 / FOM work R set: 0.7801 / SU B: 14.191 / SU ML: 0.164 / SU R Cruickshank DPI: 0.2358 / SU Rfree: 0.1953 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.236 / ESU R Free: 0.195 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2431 1670 4.9 %RANDOM
Rwork0.193 ---
obs0.1955 32497 99.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 95.74 Å2 / Biso mean: 30.69 Å2 / Biso min: 17.06 Å2
Baniso -1Baniso -2Baniso -3
1--0.66 Å20 Å2-0 Å2
2---0.66 Å20 Å2
3---1.33 Å2
Refinement stepCycle: final / Resolution: 2.1→61.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4152 0 76 367 4595
Biso mean--29.95 40.59 -
Num. residues----506
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0194335
X-RAY DIFFRACTIONr_angle_refined_deg1.3851.975835
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.7555502
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.7522.986211
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.88815792
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.0871536
X-RAY DIFFRACTIONr_chiral_restr0.0910.2635
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023318
LS refinement shellResolution: 2.099→2.153 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.335 122 -
Rwork0.286 2421 -
all-2543 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.54240.19010.17070.69690.41230.97010.02010.00980.0073-0.0091-0.0180.0079-0.0195-0.0569-0.00210.09180.0061-0.00010.1141-0.00320.000311.00760.1950.269
20.35330.15880.07620.52370.07990.32650.0083-0.0041-0.00950.0123-0.0137-0.01460.0209-0.02080.00550.13390.00720.00230.1527-0.01380.0325-17.66234.709-0.36
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A263 - 507
2X-RAY DIFFRACTION1A601 - 602
3X-RAY DIFFRACTION2B263 - 507
4X-RAY DIFFRACTION2B601 - 602
5X-RAY DIFFRACTION2A701 - 883
6X-RAY DIFFRACTION2B701 - 879
7X-RAY DIFFRACTION2C101 - 102
8X-RAY DIFFRACTION2D101 - 103

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