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- PDB-6br3: Structure of RORgt in complex with a novel inverse agonist TAK-828. -

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Basic information

Entry
Database: PDB / ID: 6br3
TitleStructure of RORgt in complex with a novel inverse agonist TAK-828.
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 / regulation of steroid metabolic process / ligand-activated transcription factor activity / Peyer's patch development / positive regulation of circadian rhythm / T-helper cell differentiation / oxysterol binding / RUNX3 Regulates Immune Response and Cell Migration / negative regulation of thymocyte apoptotic process ...cellular response to sterol / T-helper 17 cell differentiation / regulation of steroid metabolic process / ligand-activated transcription factor activity / Peyer's patch development / positive regulation of circadian rhythm / T-helper cell differentiation / 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 / DNA-binding transcription factor activity, RNA polymerase II-specific / nuclear body / 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-E3V / Nuclear receptor ROR-gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 3 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 / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)51,4526
Polymers50,2002
Non-polymers1,2514
Water724
1
A: Nuclear receptor ROR-gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,7263
Polymers25,1001
Non-polymers6262
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area790 Å2
ΔGint-13 kcal/mol
Surface area23170 Å2
MethodPISA
3
B: Nuclear receptor ROR-gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,7263
Polymers25,1001
Non-polymers6262
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)99.537, 99.537, 127.524
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: ALA / Beg label comp-ID: ALA / End auth comp-ID: CYS / End label comp-ID: CYS / Refine code: _ / Auth seq-ID: 265 - 476 / Label seq-ID: 1 - 212

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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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: 25100.047 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-E3V / {cis-3-[(5R)-5-[(7-fluoro-1,1-dimethyl-1H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carbonyl]cyclobutyl}acetic acid


Mass: 507.553 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H30FN3O5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / 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: 3.63 Å3/Da / Density % sol: 66.14 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: 3%MDP, 1.6M NaFormate, 0.1M HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 13, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→50 Å / Num. obs: 14399 / % possible obs: 100 % / Redundancy: 9.5 % / Rmerge(I) obs: 0.178 / Rpim(I) all: 0.084 / Rrim(I) all: 0.188 / Χ2: 1.003 / Net I/σ(I): 4.3 / Num. measured all: 136276
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Num. unique obsCC1/2Rpim(I) allΧ2% possible allRmerge(I) obsRrim(I) all
3-3.059.67300.4260.9610.956100
3.05-3.119.57380.4790.7650.978100
3.11-3.179.66900.5060.660.991100
3.17-3.239.57080.6350.531.016100
3.23-3.39.67190.7630.3910.983100
3.3-3.389.57180.8310.3141.0111000.9220.974
3.38-3.469.57180.8440.2590.9981000.7590.802
3.46-3.569.57210.9120.1981.0341000.580.613
3.56-3.669.67090.9350.1571.0271000.4610.487
3.66-3.789.57050.9630.131.051000.3820.404
3.78-3.919.57240.9720.1020.9741000.2990.316
3.91-4.079.57250.9820.081.0171000.2350.248
4.07-4.269.57170.9890.0641.011000.1880.199
4.26-4.489.47190.9880.0571.0161000.1640.174
4.48-4.769.47190.9910.0551.0281000.1590.168
4.76-5.139.37160.9890.0511.0181000.1470.155
5.13-5.649.17230.9920.050.9971000.1430.152
5.64-6.469.47260.9930.0470.9951000.1380.146
6.46-8.139.57280.9980.0250.9731000.0730.077
8.13-509.37460.9990.0150.9999.90.0450.047

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMACrefinement
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHASERphasing
RefinementResolution: 3→25 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.919 / SU B: 39.72 / SU ML: 0.328 / SU R Cruickshank DPI: 0.3529 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.374
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2387 709 4.9 %RANDOM
Rwork0.1957 ---
obs0.1979 13632 99.77 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 145.57 Å2 / Biso mean: 70.484 Å2 / Biso min: 36.21 Å2
Baniso -1Baniso -2Baniso -3
1--0.52 Å2-0.26 Å2-0 Å2
2---0.52 Å20 Å2
3---1.69 Å2
Refinement stepCycle: final / Resolution: 3→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3488 0 90 4 3582
Biso mean--67.13 47.4 -
Num. residues----429
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0193651
X-RAY DIFFRACTIONr_bond_other_d0.0010.023355
X-RAY DIFFRACTIONr_angle_refined_deg1.3911.9814923
X-RAY DIFFRACTIONr_angle_other_deg0.92437751
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2965427
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.88523.011176
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.12215668
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.691532
X-RAY DIFFRACTIONr_chiral_restr0.0740.2532
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.024037
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02771
Refine LS restraints NCS

Ens-ID: 1 / Number: 13754 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.06 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 3.002→3.079 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.317 61 -
Rwork0.332 994 -
all-1055 -
obs--99.43 %
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)
14.1457-2.71131.31773.4937-1.40272.0318-0.0736-0.02880.0109-0.00730.04440.05120.0372-0.22830.02920.0773-0.0476-0.01310.06060.00160.005512.473281.695-1.3623
23.4552.8584-1.78034.2871-1.31292.2478-0.08760.0751-0.0769-0.0582-0.04920.14590.0848-0.14360.13680.07170.0267-0.00890.0996-0.03040.032712.302385.994434.2473
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A265 - 480
2X-RAY DIFFRACTION2B265 - 477

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