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- PDB-6cvh: Identification and biological evaluation of thiazole-based invers... -

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Basic information

Entry
Database: PDB / ID: 6cvh
TitleIdentification and biological evaluation of thiazole-based inverse agonists of RORgt
ComponentsNuclear receptor ROR-gamma
KeywordsNUCLEAR PROTEIN / Nuclear Receptor RORgt
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-FJG / Nuclear receptor ROR-gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / SAD / Resolution: 3.5 Å
AuthorsSpurlino, J. / Milligan, C.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2018
Title: Identification and biological evaluation of thiazole-based inverse agonists of ROR gamma t.
Authors: Gege, C. / Cummings, M.D. / Albers, M. / Kinzel, O. / Kleymann, G. / Schluter, T. / Steeneck, C. / Nelen, M.I. / Milligan, C. / Spurlino, J. / Xue, X. / Leonard, K. / Edwards, J.P. / Fourie, ...Authors: Gege, C. / Cummings, M.D. / Albers, M. / Kinzel, O. / Kleymann, G. / Schluter, T. / Steeneck, C. / Nelen, M.I. / Milligan, C. / Spurlino, J. / Xue, X. / Leonard, K. / Edwards, J.P. / Fourie, A. / Goldberg, S.D. / Hoffmann, T.
History
DepositionMar 28, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 25, 2018Provider: repository / Type: Initial release
Revision 1.1May 2, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
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

Downloads & links

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Assembly

Deposited unit
A: Nuclear receptor ROR-gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,0272
Polymers26,4361
Non-polymers5921
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)92.378, 92.378, 141.898
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: 26435.604 Da / Num. of mol.: 1
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-FJG / trans-3-({4-(cyclohexylmethyl)-5-[3-(1-methylcyclopropyl)-5-{[(2R)-1,1,1-trifluoropropan-2-yl]carbamoyl}phenyl]-1,3-thiazole-2-carbonyl}amino)cyclobutane-1-carboxylic acid


Mass: 591.685 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H36F3N3O4S / Feature type: SUBJECT OF INVESTIGATION

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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: 3.31 Å3/Da / Density % sol: 62.79 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 1.35M NaFormate, 0.1M Hepes pH7, 3%MPD

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Data collection

DiffractionMean temperature: 80 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 8, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.5→40.001 Å / Num. obs: 4898 / % possible obs: 99.7 % / Redundancy: 17.2 % / Net I/σ(I): 9.9
Reflection shellResolution: 3.5→3.56 Å

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Processing

Software
NameVersionClassification
PHENIXrefinement
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: SAD / Resolution: 3.5→40.001 Å / SU ML: 0.52 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 33.14
RfactorNum. reflection% reflection
Rfree0.3096 486 9.97 %
Rwork0.2598 --
obs0.2649 4875 99.25 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 170.94 Å2 / Biso mean: 86.9507 Å2 / Biso min: 48.85 Å2
Refinement stepCycle: final / Resolution: 3.5→40.001 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1852 0 76 0 1928
Biso mean--74.03 --
Num. residues----227
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0021934
X-RAY DIFFRACTIONf_angle_d0.4282609
X-RAY DIFFRACTIONf_chiral_restr0.029284
X-RAY DIFFRACTIONf_plane_restr0.003330
X-RAY DIFFRACTIONf_dihedral_angle_d17.9591170
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 3

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.5-4.0060.36091550.30691399155498
4.006-5.04560.33951580.25614341592100
5.0456-40.00340.26831730.242715561729100
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)
13.6846-1.2439-0.82222.7593-0.27981.22310.28321.05630.1541-0.2394-0.31790.1297-1.0551-0.04650.02081.09090.25840.01380.5872-0.08880.808735.9974-23.3079-0.0402
22.8339-0.74110.84611.81580.78913.05710.1113-0.75090.92240.7409-0.20180.4022-1.0394-0.29470.17111.16440.21620.07150.81860.02170.8075.3447-19.7886-7.6702
34.51980.08952.41050.21020.57582.7613-0.14840.57990.7584-0.86630.23780.2432-0.1468-0.1689-0.04910.9929-0.04720.07110.48610.20990.802215.4934-28.3729-16.5401
47.1508-0.2217-1.49273.19790.92692.97391.0832-0.3065-0.08520.0021-0.5835-0.07180.14170.0361-0.470.8677-0.0835-0.08870.75930.06650.561627.6197-33.5783-10.4648
52.3-0.41323.18641.35221.00016.6664-0.48360.0170.30660.9805-0.32290.65160.05330.3530.8991.1079-0.05150.01620.65220.11080.74933.3893-26.5879-5.4945
62.71621.157-0.3782.39892.03593.55920.3024-0.2337-0.20360.9388-0.50850.38091.0406-0.59560.14680.6950.11720.01410.76860.14191.017816.6921-31.60970.574
71.395-1.1586-0.74843.27682.50164.0599-0.1386-0.1862-0.32360.84970.05930.29321.0849-0.6209-0.11380.87190.105-0.10040.9979-0.010.704232.0768-36.40361.9436
86.29430.75082.8683.36361.5454.9640.69590.8047-1.31610.5790.4578-0.02651.07310.7223-1.25761.2216-0.0963-0.07320.9356-0.08730.759512.9921-42.0866-13.725
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 265 through 283 )A265 - 283
2X-RAY DIFFRACTION2chain 'A' and (resid 284 through 312 )A284 - 312
3X-RAY DIFFRACTION3chain 'A' and (resid 313 through 337 )A313 - 337
4X-RAY DIFFRACTION4chain 'A' and (resid 338 through 368 )A338 - 368
5X-RAY DIFFRACTION5chain 'A' and (resid 369 through 393 )A369 - 393
6X-RAY DIFFRACTION6chain 'A' and (resid 394 through 425 )A394 - 425
7X-RAY DIFFRACTION7chain 'A' and (resid 426 through 470 )A426 - 470
8X-RAY DIFFRACTION8chain 'A' and (resid 471 through 491 )A471 - 491

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