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- PDB-6br2: Structure of RORgt in complex with a novel isoquinoline inverse a... -

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Basic information

Entry
Database: PDB / ID: 6br2
TitleStructure of RORgt in complex with a novel isoquinoline inverse agonist.
ComponentsNuclear receptor ROR-gamma
Keywordstranscription/agonist / Nuclear Hormone Receptor / inverse agonist / complex / transcription-agonist complex
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-E3S / Nuclear receptor ROR-gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 3.18 Å
AuthorsSkene, R.J. / Hoffman, I.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of [ cis-3-({(5 R)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic Acid (TAK-828F) as a ...Title: Discovery of [ cis-3-({(5 R)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor gamma t Inverse Agonist.
Authors: Kono, M. / Ochida, A. / Oda, T. / Imada, T. / Banno, Y. / Taya, N. / Masada, S. / Kawamoto, T. / Yonemori, K. / Nara, Y. / Fukase, Y. / Yukawa, T. / Tokuhara, H. / Skene, R. / Sang, B.C. / ...Authors: Kono, M. / Ochida, A. / Oda, T. / Imada, T. / Banno, Y. / Taya, N. / Masada, S. / Kawamoto, T. / Yonemori, K. / Nara, Y. / Fukase, Y. / Yukawa, T. / Tokuhara, H. / Skene, R. / Sang, B.C. / Hoffman, I.D. / Snell, G.P. / Uga, K. / Shibata, A. / Igaki, K. / Nakamura, Y. / Nakagawa, H. / Tsuchimori, N. / Yamasaki, M. / Shirai, J. / Yamamoto, S.
History
DepositionNov 29, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 21, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 25, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Mar 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

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Assembly

Deposited unit
A: Nuclear receptor ROR-gamma
B: Nuclear receptor ROR-gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,2016
Polymers50,0022
Non-polymers1,1994
Water32418
1
A: Nuclear receptor ROR-gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,6013
Polymers25,0011
Non-polymers6002
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Nuclear receptor ROR-gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,6013
Polymers25,0011
Non-polymers6002
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)99.842, 99.842, 125.484
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61

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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: 25000.916 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: Chemical ChemComp-MPD / (4S)-2-METHYL-2,4-PENTANEDIOL


Mass: 118.174 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H14O2 / Comment: precipitant*YM
#3: Chemical ChemComp-E3S / (1R)-N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-[(3-oxo-2,3-dihydro-1,2-oxazol-5-yl)acetyl]-1,2,3,4-tetrahydroisoquinoline-1-carboxamide


Mass: 481.516 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H28FN3O5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 18 / 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: 3.61 Å3/Da / Density % sol: 65.94 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: 2%MPD, 1.2M NaFormate, 0.1M Hepes 7.5

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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: Jun 29, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 3.18→50 Å / Num. obs: 12017 / % possible obs: 100 % / Redundancy: 4.7 % / Rmerge(I) obs: 0.061 / Χ2: 1.004 / Net I/σ(I): 11.9 / Num. measured all: 56433
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
3.18-3.234.80.945871.0121100
3.23-3.294.80.6646000.9821100
3.29-3.364.80.6115961.0291100
3.36-3.434.80.4895911.0351100
3.43-3.54.80.3665981.0641100
3.5-3.584.80.2826010.9471100
3.58-3.674.70.2135970.9891100
3.67-3.774.80.185881.0221100
3.77-3.884.80.1346080.9791100
3.88-4.014.70.1096180.991100
4.01-4.154.80.0765820.9431100
4.15-4.324.70.0736031.0121100
4.32-4.514.70.0645910.9821100
4.51-4.754.70.0626091.0231100
4.75-5.054.60.0656021.0291100
5.05-5.444.60.0665991.0171100
5.44-5.984.60.0696081.091100
5.98-6.854.40.0445930.9721100
6.85-8.624.60.0256160.9791100
8.62-504.60.0176300.993199.7

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMACrefinement
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHASERphasing
RefinementResolution: 3.18→43.23 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.949 / WRfactor Rfree: 0.2164 / WRfactor Rwork: 0.173 / FOM work R set: 0.8175 / SU B: 43.838 / SU ML: 0.323 / SU R Cruickshank DPI: 0.3998 / SU Rfree: 0.4114 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.411 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2271 589 4.9 %RANDOM
Rwork0.175 ---
obs0.1775 11396 99.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 217.19 Å2 / Biso mean: 107.687 Å2 / Biso min: 60.92 Å2
Baniso -1Baniso -2Baniso -3
1-0.6 Å20.3 Å20 Å2
2--0.6 Å2-0 Å2
3----1.96 Å2
Refinement stepCycle: final / Resolution: 3.18→43.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3475 0 86 18 3579
Biso mean--103.01 102.21 -
Num. residues----427
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0193632
X-RAY DIFFRACTIONr_angle_refined_deg1.3071.9794893
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.5265425
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.14123.011176
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.74515666
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6921532
X-RAY DIFFRACTIONr_chiral_restr0.080.2529
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022714
LS refinement shellResolution: 3.179→3.261 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.409 47 -
Rwork0.292 830 -
all-877 -
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)
14.24850.47051.79841.43210.64741.0065-0.151-0.05030.1210.0445-0.05970.1017-0.0152-0.03490.21080.0378-0.03820.05150.0857-0.02370.1696-18.597-32.059-2.682
20.8932-0.62630.67593.9865-1.8991.21710.0162-0.06140.1051-0.0791-0.0806-0.14810.0754-0.04320.06440.057-0.0043-0.03850.0820.0290.0914-22.213-29.70931.911
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A265 - 479
2X-RAY DIFFRACTION1A501 - 502
3X-RAY DIFFRACTION2B265 - 476
4X-RAY DIFFRACTION2B501 - 502
5X-RAY DIFFRACTION2A601 - 608
6X-RAY DIFFRACTION2B601 - 610

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