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- PDB-5m96: Synthesis and biological evaluation of new triazolo and imidazolo... -

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Basic information

Entry
Database: PDB / ID: 5m96
TitleSynthesis and biological evaluation of new triazolo and imidazolopyridine RORgt inverse agonists
ComponentsNuclear receptor ROR-gamma
KeywordsTRANSCRIPTION / nuclear hormone receptor / ligand-binding domain / inverse agonist
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-Q6Y / Nuclear receptor ROR-gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.77 Å
AuthorsKallen, J.
CitationJournal: ChemMedChem / Year: 2016
Title: Synthesis and Biological Evaluation of New Triazolo- and Imidazolopyridine ROR gamma t Inverse Agonists.
Authors: Hintermann, S. / Guntermann, C. / Mattes, H. / Carcache, D.A. / Wagner, J. / Vulpetti, A. / Billich, A. / Dawson, J. / Kaupmann, K. / Kallen, J. / Stringer, R. / Orain, D.
History
DepositionOct 31, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 14, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 28, 2016Group: Database references
Revision 2.0Dec 19, 2018Group: Atomic model / Data collection / Derived calculations
Category: atom_site / pdbx_nonpoly_scheme ...atom_site / pdbx_nonpoly_scheme / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.label_alt_id / _pdbx_nonpoly_scheme.auth_seq_num
Revision 2.1May 8, 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)55,5106
Polymers53,6082
Non-polymers1,9024
Water6,287349
1
A: Nuclear receptor ROR-gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,7553
Polymers26,8041
Non-polymers9512
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Nuclear receptor ROR-gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,7553
Polymers26,8041
Non-polymers9512
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)100.017, 100.017, 115.686
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: 26803.945 Da / Num. of mol.: 2
Fragment: C-terminal domain, ligand binding domain, UNP residues 263-491
Mutation: C455S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RORC, NR1F3, RORG, RZRG / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: P51449
#2: Chemical
ChemComp-Q6Y / ~{N}-[8-[[(3~{S})-4-cyclopentylcarbonyl-3-methyl-piperazin-1-yl]methyl]-7-methyl-imidazo[1,2-a]pyridin-6-yl]-2-methyl-pyrimidine-5-carboxamide


Mass: 475.586 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H33N7O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 349 / 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: 3.12 Å3/Da / Density % sol: 60.52 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 1.75M NaFormate, 0.1M PIPES

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00003 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Dec 12, 2015
RadiationMonochromator: SI 111 channel / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 1.77→19.87 Å / Num. obs: 63761 / % possible obs: 99.9 % / Redundancy: 10.2 % / Biso Wilson estimate: 34.6 Å2 / Rmerge(I) obs: 0.053 / Net I/σ(I): 26.3
Reflection shellResolution: 1.77→1.82 Å / Redundancy: 10.2 % / Rmerge(I) obs: 0.903 / Mean I/σ(I) obs: 2.8 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.2data extraction
XSCALEdata scaling
XSCALEdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.77→19.28 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.957 / SU B: 2.062 / SU ML: 0.066 / SU R Cruickshank DPI: 0.1077 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.108 / ESU R Free: 0.099
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2078 3187 5 %RANDOM
Rwork0.1921 ---
obs0.1929 60571 99.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 67.66 Å2 / Biso mean: 28.534 Å2 / Biso min: 15.28 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3----0.01 Å2
Refinement stepCycle: final / Resolution: 1.77→19.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3662 0 140 349 4151
Biso mean--26.47 38.83 -
Num. residues----448
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0213989
X-RAY DIFFRACTIONr_angle_refined_deg0.921.9945411
X-RAY DIFFRACTIONr_dihedral_angle_1_deg3.8015486
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.13723.073192
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.74315730
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0331535
X-RAY DIFFRACTIONr_chiral_restr0.0640.2585
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023031
X-RAY DIFFRACTIONr_mcbond_it0.9662.5791830
X-RAY DIFFRACTIONr_mcangle_it1.5743.862294
X-RAY DIFFRACTIONr_scbond_it1.5042.8672159
LS refinement shellResolution: 1.77→1.816 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.293 233 -
Rwork0.295 4440 -
all-4673 -
obs--100 %

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