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- PDB-6vsw: Optimization and biological evaluation of thiazole-bis-amide inve... -

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Basic information

Entry
Database: PDB / ID: 6vsw
TitleOptimization and biological evaluation of thiazole-bis-amide inverse agonists of RORgt
ComponentsRAR-related orphan receptor C
KeywordsNUCLEAR PROTEIN / Nuclear Receptor RORgt
Function / homology
Function and homology information


multicellular organism development / T-helper 17 cell differentiation / ligand-activated transcription factor activity / cellular response to sterol / regulation of steroid metabolic process / Peyer's patch development / positive regulation of circadian rhythm / oxysterol binding / T-helper cell differentiation / RUNX3 Regulates Immune Response and Cell Migration ...multicellular organism development / T-helper 17 cell differentiation / ligand-activated transcription factor activity / cellular response to sterol / regulation of steroid metabolic process / Peyer's patch development / positive regulation of circadian rhythm / oxysterol binding / T-helper cell differentiation / 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 / circadian rhythm / nuclear receptor activity / sequence-specific double-stranded DNA binding / Interleukin-4 and Interleukin-13 signaling / sequence-specific DNA binding / 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-RG7 / Nuclear receptor ROR-gamma / RAR-related orphan receptor C
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.202 Å
AuthorsSpurlino, J. / Milligan, C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Optimization and biological evaluation of thiazole-bis-amide inverse agonists of ROR gamma t.
Authors: Gege, C. / Albers, M. / Kinzel, O. / Kleymann, G. / Schluter, T. / Steeneck, C. / Hoffmann, T. / Xue, X. / Cummings, M.D. / Spurlino, J. / Milligan, C. / Fourie, A.M. / Edwards, J.P. / ...Authors: Gege, C. / Albers, M. / Kinzel, O. / Kleymann, G. / Schluter, T. / Steeneck, C. / Hoffmann, T. / Xue, X. / Cummings, M.D. / Spurlino, J. / Milligan, C. / Fourie, A.M. / Edwards, J.P. / Leonard, K. / Coe, K. / Scott, B. / Pippel, D. / Goldberg, S.D.
History
DepositionFeb 12, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 13, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 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

Downloads & links

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Assembly

Deposited unit
A: RAR-related orphan receptor C
B: RAR-related orphan receptor C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,4524
Polymers54,1532
Non-polymers1,2992
Water00
1
A: RAR-related orphan receptor C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,7262
Polymers27,0761
Non-polymers6501
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: RAR-related orphan receptor C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,7262
Polymers27,0761
Non-polymers6501
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)100.261, 100.261, 124.585
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 RAR-related orphan receptor C / RORC protein


Mass: 27076.307 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RORC / Production host: Escherichia coli (E. coli) / References: UniProt: Q6I9R9, UniProt: P51449*PLUS
#2: Chemical ChemComp-RG7 / 5-(2,3-dichloro-4-{[(2S)-1,1,1-trifluoropropan-2-yl]sulfamoyl}phenyl)-4-(4-fluoropiperidine-1-carbonyl)-N-(2-hydroxy-2-methylpropyl)-1,3-thiazole-2-carboxamide


Mass: 649.506 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H26Cl2F4N4O5S2 / Feature type: SUBJECT OF INVESTIGATION
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: 3.34 Å3/Da / Density % sol: 63.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 1.35M NaFormate, 0.1M Hepes pH7, 3%MPD

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 13, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.2→50 Å / Num. obs: 11779 / % possible obs: 100 % / Redundancy: 9.8 % / Biso Wilson estimate: 113.22 Å2 / Rmerge(I) obs: 0.136 / Χ2: 1.474 / Net I/σ(I): 4.5 / Num. measured all: 115470
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
3.2-3.269.60.7465890.499199.8
3.26-3.319.70.9935840.5191100
3.31-3.389.90.9155830.5691100
3.38-3.459.80.6875950.5751100
3.45-3.529.70.6175710.6781100
3.52-3.69.20.5535870.7241100
3.6-3.699.40.4275860.8721100
3.69-3.79100.3665950.9521100
3.79-3.919.50.3135761.1861100
3.91-4.0310.10.2575901.2751100
4.03-4.1810.50.2125821.4831100
4.18-4.3410.40.1865991.6991100
4.34-4.5410.30.1825912.0341100
4.54-4.7810.10.1665752.0731100
4.78-5.089.70.165861.9871100
5.08-5.479.40.1555882.0861100
5.47-6.029.50.1615921.8851100
6.02-6.8910.50.1255962.041100
6.89-8.67100.095982.4711100
8.67-5090.0776163.7531100

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Processing

Software
NameVersionClassification
HKL-2000data reduction
SCALEPACKdata scaling
PHENIX1.12_2829refinement
PDB_EXTRACT3.25data extraction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6NAD

6nad


Resolution: 3.202→43.414 Å / SU ML: 0.48 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 29.09
RfactorNum. reflection% reflection
Rfree0.2313 1180 10.07 %
Rwork0.1857 --
obs0.1904 11717 99.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 233.51 Å2 / Biso mean: 117.3787 Å2 / Biso min: 69.18 Å2
Refinement stepCycle: final / Resolution: 3.202→43.414 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3705 0 132 0 3837
Biso mean--145.8 --
Num. residues----453
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0023863
X-RAY DIFFRACTIONf_angle_d0.4795212
X-RAY DIFFRACTIONf_chiral_restr0.028562
X-RAY DIFFRACTIONf_plane_restr0.003657
X-RAY DIFFRACTIONf_dihedral_angle_d20.7452360
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
3.2024-3.34810.36761450.3084131799
3.3481-3.52450.30321420.2572130099
3.5245-3.74530.28061500.22821312100
3.7453-4.03420.25821500.20061308100
4.0342-4.43990.25861490.17281317100
4.4399-5.08150.23111440.17831315100
5.0815-6.39880.25031490.20221329100
6.3988-100.17471510.15051339100
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)
17.58010.664-0.46935.98285.02424.20720.42080.82580.0861-0.7866-0.51230.44580.0426-1.958-0.26391.03560.057-0.00621.45150.19850.8298-46.4485131.99485.0406
23.7225-1.1286-2.17928.52640.74463.3803-0.06390.064-0.4458-0.02670.15060.8880.476-0.3073-0.02021.1249-0.0165-0.09871.0989-0.05141.0335-33.071108.4272-5.3137
34.36464.3632-4.59264.274-4.5284.79160.1252-0.72741.63010.00630.50580.4596-1.9254-1.086-0.63551.33490.33510.0720.97820.02561.2057-33.6931134.5683-9.1142
44.0098-3.28070.7157.33243.62714.57290.2055-0.5764-0.5220.4626-0.03990.6096-0.1412-0.433-0.17731.0204-0.00980.11291.10640.11090.9957-31.5392110.41482.3993
53.9894-4.7369-1.61837.43793.96641.6402-0.131-0.8439-0.16630.72640.29230.24930.32660.3814-0.14891.20410.20410.10871.04110.11330.7481-27.7694114.90734.5472
62.4866-0.2297-1.72732.97972.58813.2203-0.32730.2760.24981.18890.3569-0.4815-1.13072.3201-0.83111.13070.08260.16791.7802-0.11851.3939-26.966137.9277-4.0977
74.8528-1.8473-0.31267.9335-2.4336.1039-0.6287-0.3424-0.10590.97850.6752-0.0315-0.0543-0.4904-0.06220.91260.2117-0.01511.213-0.01940.8516-34.9367133.00889.9871
83.9206-2.31451.88483.5941-0.41543.88120.60310.3520.0921-0.5582-0.1875-2.1241-0.71880.57360.24631.1365-0.03590.12961.11240.1180.8769-19.8087119.3893-7.632
93.54644.1297-3.72699.3492-5.82734.36010.4223-0.4086-1.3130.8201-1.4261-1.3980.87851.65451.18521.02670.2975-0.08860.93990.11041.0346-16.9461117.1449-36.9224
105.51762.80972.52522.23381.35230.74880.17550.3777-0.40730.09260.07990.03830.35960.0288-0.28511.1063-0.01240.07911.16880.03841.0859-44.4025113.5368-27.8598
119.67255.9324.97643.79864.47189.98631.06280.2025-0.20770.4586-0.6637-0.91210.00121.3362-0.33520.79020.0373-0.00821.2579-0.07761.0999-25.4962126.9797-25.6159
126.0451.9787-3.01341.1133-0.42413.1859-0.40580.8074-0.2201-0.32680.36060.15420.7628-0.6327-0.07040.8462-0.00360.00361.1054-0.07720.9124-42.6254119.08-37.2358
136.73192.881-0.16874.5792.96639.4878-0.03480.02890.0392-0.1952-0.07050.8134-0.8063-0.23730.03510.99390.11470.02841.15220.01010.958-19.894130.7588-35.8777
149.0214-0.7152-3.70584.8718-1.19813.88511.10650.5902-0.08530.0317-0.50810.2711-1.7929-0.1047-0.87230.84920.092-0.02330.8389-0.09880.9272-37.894128.9716-34.9585
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 265 through 282 )A265 - 282
2X-RAY DIFFRACTION2chain 'A' and (resid 283 through 337 )A283 - 337
3X-RAY DIFFRACTION3chain 'A' and (resid 338 through 356 )A338 - 356
4X-RAY DIFFRACTION4chain 'A' and (resid 357 through 384 )A357 - 384
5X-RAY DIFFRACTION5chain 'A' and (resid 385 through 425 )A385 - 425
6X-RAY DIFFRACTION6chain 'A' and (resid 426 through 435 )A426 - 435
7X-RAY DIFFRACTION7chain 'A' and (resid 436 through 470 )A436 - 470
8X-RAY DIFFRACTION8chain 'A' and (resid 471 through 492 )A471 - 492
9X-RAY DIFFRACTION9chain 'B' and (resid 265 through 283 )B265 - 283
10X-RAY DIFFRACTION10chain 'B' and (resid 284 through 336 )B284 - 336
11X-RAY DIFFRACTION11chain 'B' and (resid 337 through 363 )B337 - 363
12X-RAY DIFFRACTION12chain 'B' and (resid 364 through 425 )B364 - 425
13X-RAY DIFFRACTION13chain 'B' and (resid 426 through 456 )B426 - 456
14X-RAY DIFFRACTION14chain 'B' and (resid 457 through 489 )B457 - 489

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