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- PDB-8d8i: Crystal structure of Reverb alpha in complex with synthetic agonist -

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Basic information

Entry
Database: PDB / ID: 8d8i
TitleCrystal structure of Reverb alpha in complex with synthetic agonist
Components
  • Nuclear receptor corepressor 1
  • Nuclear receptor subfamily 1 group D member 1
KeywordsTRANSCRIPTION / REV-ERB / Nuclear receptor / Agonist
Function / homology
Function and homology information


regulation of circadian sleep/wake cycle / positive regulation of bile acid biosynthetic process / NR1D1 (REV-ERBA) represses gene expression / circadian temperature homeostasis / regulation of type B pancreatic cell proliferation / negative regulation of astrocyte activation / negative regulation of microglial cell activation / Loss of MECP2 binding ability to the NCoR/SMRT complex / response to leptin / negative regulation of neuroinflammatory response ...regulation of circadian sleep/wake cycle / positive regulation of bile acid biosynthetic process / NR1D1 (REV-ERBA) represses gene expression / circadian temperature homeostasis / regulation of type B pancreatic cell proliferation / negative regulation of astrocyte activation / negative regulation of microglial cell activation / Loss of MECP2 binding ability to the NCoR/SMRT complex / response to leptin / negative regulation of neuroinflammatory response / negative regulation of toll-like receptor 4 signaling pathway / negative regulation of androgen receptor signaling pathway / regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of JNK cascade / glycogen biosynthetic process / negative regulation of glycolytic process / negative regulation of cold-induced thermogenesis / regulation of fat cell differentiation / nuclear thyroid hormone receptor binding / nuclear steroid receptor activity / negative regulation of fatty acid metabolic process / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / Notch-HLH transcription pathway / E-box binding / intracellular glucose homeostasis / locomotor rhythm / histone deacetylase complex / Regulation of MECP2 expression and activity / regulation of lipid metabolic process / cellular response to interleukin-1 / spindle assembly / proteasomal protein catabolic process / negative regulation of canonical NF-kappaB signal transduction / Nuclear signaling by ERBB4 / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / transcription repressor complex / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / transcription corepressor binding / negative regulation of miRNA transcription / cholesterol homeostasis / nuclear receptor binding / HDACs deacetylate histones / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Downregulation of SMAD2/3:SMAD4 transcriptional activity / circadian regulation of gene expression / Heme signaling / protein destabilization / Transcriptional activation of mitochondrial biogenesis / regulation of circadian rhythm / PPARA activates gene expression / Cytoprotection by HMOX1 / NOTCH1 Intracellular Domain Regulates Transcription / mitotic spindle / DNA-binding transcription repressor activity, RNA polymerase II-specific / histone deacetylase binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / transcription corepressor activity / nuclear receptor activity / sequence-specific double-stranded DNA binding / Circadian Clock / cellular response to tumor necrosis factor / chromatin organization / cellular response to lipopolysaccharide / RNA polymerase II-specific DNA-binding transcription factor binding / dendritic spine / cell differentiation / nuclear body / DNA-binding transcription factor activity, RNA polymerase II-specific / transcription cis-regulatory region binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of DNA-templated transcription / dendrite / heme binding / chromatin / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / membrane / nucleus / cytosol / cytoplasm
Similarity search - Function
N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / SANT domain profile. / SANT domain / Myb domain / Myb-like DNA-binding domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / : ...N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / SANT domain profile. / SANT domain / Myb domain / Myb-like DNA-binding domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / : / Homeobox-like domain superfamily / 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
Similarity search - Domain/homology
Chem-QFX / Nuclear receptor corepressor 1 / Nuclear receptor subfamily 1 group D member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.504 Å
AuthorsRonin, C. / Ciesielski, F. / Hegazy, L. / Burris, P.T.
Funding support1items
OrganizationGrant numberCountry
Not fundedW81XWH-19-1-0632
CitationJournal: Nat Commun / Year: 2022
Title: Structural basis of synthetic agonist activation of the nuclear receptor REV-ERB.
Authors: Murray, M.H. / Valfort, A.C. / Koelblen, T. / Ronin, C. / Ciesielski, F. / Chatterjee, A. / Veerakanellore, G.B. / Elgendy, B. / Walker, J.K. / Hegazy, L. / Burris, T.P.
History
DepositionJun 8, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 14, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Nuclear receptor subfamily 1 group D member 1
B: Nuclear receptor corepressor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,0943
Polymers28,7712
Non-polymers3231
Water46826
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2130 Å2
ΔGint-18 kcal/mol
Surface area10520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.073, 115.073, 107.32
Angle α, β, γ (deg.)90, 90, 120
Int Tables number155
Space group name H-MH32

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Components

#1: Protein Nuclear receptor subfamily 1 group D member 1 / Rev-erbA-alpha / V-erbA-related protein 1 / EAR-1


Mass: 26490.156 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1D1, EAR1, HREV, THRAL / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P20393
#2: Protein/peptide Nuclear receptor corepressor 1 / N-CoR / N-CoR1


Mass: 2280.601 Da / Num. of mol.: 1 / Mutation: C2056A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NCOR1, KIAA1047 / Production host: Escherichia coli (E. coli) / References: UniProt: O75376
#3: Chemical ChemComp-QFX / (4S)-6-[([1,1'-biphenyl]-2-yl)oxy]-3-chloro[1,2,4]triazolo[4,3-b]pyridazine


Mass: 322.748 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H11ClN4O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 26 / Source method: isolated from a natural source / Formula: H2O
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: 2.38 Å3/Da / Density % sol: 48.24 %
Crystal growTemperature: 295.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 80mM Na Hepes pH7.5, 200mM proline, 8% glycerol and 18% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.9786 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 2.504→73.027 Å / Num. obs: 7248 / % possible obs: 85.5 % / Redundancy: 8.11 %
Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last ...Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last updated 2020-04-13: http://mmcif.wwpdb.org/dictionaries/mmcif_pdbx_v50.dic/Index/) and the actual quantities provided by MRFANA (https://github.com/githubgphl/MRFANA) from the autoPROC package (https://www.globalphasing.com/autoproc/). In general, the mmCIF categories here should provide items that are currently used in the PDB archive. If there are alternatives, the one recommended by the PDB developers has been selected. The distinction between *_all and *_obs quantities is not always clear: often only one version is actively used within the PDB archive (or is the one recommended by PDB developers). The intention of distinguishing between classes of reflections before and after some kind of observation criterion was applied, can in principle be useful - but such criteria change in various ways throughout the data processing steps (rejection of overloaded or too partial reflections, outlier/misfit rejections during scaling etc) and there is no retrospect computation of data scaling/merging statistics for the reflections used in the final refinement (where another observation criterion might have been applied). Typical data processing will usually only provide one version of statistics at various stages and these are given in the recommended item here, irrespective of the "_all" and "_obs" connotation, see e.g. the use of _reflns.pdbx_Rmerge_I_obs, _reflns.pdbx_Rrim_I_all and _reflns.pdbx_Rpim_I_all. Please note that all statistics related to "merged intensities" (or "merging") are based on inverse-variance weighting of the individual measurements making up a symmetry-unique reflection. This is standard for several decades now, even if some of the dictionary definitions seem to suggest that a simple "mean" or "average" intensity is being used instead. R-values are always given for all symmetry-equivalent reflections following Friedel's law, i.e. Bijvoet pairs are not treated separately (since we want to describe the overall mean intensity and not the mean I(+) and I(-) here). The Rrim metric is identical to the Rmeas R-value and only differs in name. _reflns.pdbx_number_measured_all is the number of measured intensities just before the final merging step (at which point no additional rejection takes place). _reflns.number_obs is the number of symmetry-unique observations, i.e. the result of merging those measurements via inverse-variance weighting. _reflns.pdbx_netI_over_sigmaI is based on the merged intensities (_reflns.number_obs) as expected. _reflns.pdbx_redundancy is synonymous with "multiplicity". The per-shell item _reflns_shell.number_measured_all corresponds to the overall value _reflns.pdbx_number_measured_all. The per-shell item _reflns_shell.number_unique_all corresponds to the overall value _reflns.number_obs. The per-shell item _reflns_shell.percent_possible_all corresponds to the overall value _reflns.percent_possible_obs. The per-shell item _reflns_shell.meanI_over_sigI_obs corresponds to the overall value given as _reflns.pdbx_netI_over_sigmaI. But be aware of the incorrect definition of the former in the current dictionary!
CC1/2: 0.999 / CC1/2 anomalous: -0.069 / Rmerge(I) obs: 0.0691 / Rpim(I) all: 0.0258 / Rrim(I) all: 0.0741 / AbsDiff over sigma anomalous: 0.779 / Baniso tensor eigenvalue 1: 86.5 Å2 / Baniso tensor eigenvalue 2: 86.5 Å2 / Baniso tensor eigenvalue 3: 68.8 Å2 / Baniso tensor eigenvector 1 ortho1: 1 / Baniso tensor eigenvector 1 ortho2: 0 / Baniso tensor eigenvector 1 ortho3: 0 / Baniso tensor eigenvector 2 ortho1: 0 / Baniso tensor eigenvector 2 ortho2: 1 / Baniso tensor eigenvector 2 ortho3: 0 / Baniso tensor eigenvector 3 ortho1: 0 / Baniso tensor eigenvector 3 ortho2: 0 / Baniso tensor eigenvector 3 ortho3: 1 / Aniso diffraction limit 1: 2.704 Å / Aniso diffraction limit 2: 2.704 Å / Aniso diffraction limit 3: 2.413 Å / Aniso diffraction limit axis 1 ortho1: 1 / Aniso diffraction limit axis 1 ortho2: 0 / Aniso diffraction limit axis 1 ortho3: 0 / Aniso diffraction limit axis 2 ortho1: 0 / Aniso diffraction limit axis 2 ortho2: 1 / Aniso diffraction limit axis 2 ortho3: 0 / Aniso diffraction limit axis 3 ortho1: 0 / Aniso diffraction limit axis 3 ortho2: 0 / Aniso diffraction limit axis 3 ortho3: 1 / Net I/σ(I): 18.44 / Num. measured all: 58812 / Observed signal threshold: 1.2 / Orthogonalization convention: pdb / % possible anomalous: 83.2 / % possible ellipsoidal: 85.5 / % possible ellipsoidal anomalous: 83.2 / % possible spherical: 75.7 / % possible spherical anomalous: 73.2 / Redundancy anomalous: 4.33 / Signal type: local
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. measured obsNum. unique allNum. unique obsCC1/2CC1/2 anomalousRpim(I) allRrim(I) allAbsDiff over sigma anomalous% possible anomalous% possible ellipsoidal% possible ellipsoidal anomalous% possible spherical% possible spherical anomalousRedundancy anomalous% possible all
7.458-73.0276.970.028551.19268226823853850.999-0.1130.0110.03070.72591969196914.0996
5.93-7.4587.70.039740.14287328733733730.9990.0560.01480.04260.75595.999.295.999.295.94.2699.2
5.167-5.937.720.046237.4288828883743740.998-0.040.01740.04960.81697.210097.210097.24.2100
4.696-5.1678.120.044539.48299029903683680.999-0.040.01650.04770.72697.599.797.599.797.54.3899.7
4.358-4.6967.940.048435.58289028903643640.9990.1050.01820.0520.77897.510097.510097.54.25100
4.103-4.3588.030.055933.1296329633693690.998-0.1230.02090.05990.78497.610097.610097.64.28100
3.894-4.1037.720.07526.84284928493693690.997-0.0330.02920.08090.81297.610097.610097.64.14100
3.724-3.8948.120.091823.02291629163593590.995-0.0280.03450.09840.83198.210098.210098.24.27100
3.578-3.7248.120.131818.79293329333613610.989-0.1340.04940.14140.7998.210098.210098.24.28100
3.363-3.5787.840.180913.41291729173723720.9890.0570.06830.19420.77253.754.953.754.953.74.1954.9
3.264-3.3637.930.2549.56288028803633630.9780.0250.09540.27220.8699799.79799.7974.299.7
3.18-3.2648.160.32747.36293829383603600.961-0.0570.1210.35020.76896.199.796.199.796.14.3499.7
3.1-3.188.290.4026.25298429843603600.9640.0530.14740.42940.7759799.79799.7974.3899.7
3.028-3.17.660.45544.95277427743623620.933-0.060.17310.48870.77996.710096.710096.74.07100
2.965-3.0288.080.59883.68286028603543540.901-0.0580.22060.63990.78697.510097.510097.54.28100
2.905-2.9658.270.77172.82295129513573570.833-0.0270.28180.82410.799710097100974.33100
2.851-2.9058.370.8742.52296329633543540.801-0.0290.31590.93150.73496.197.896.197.896.14.3997.8
2.793-2.8518.690.98442.24302430243483480.7680.0880.34881.04680.7887.888.887.888.887.84.5288.8
2.734-2.7939.431.08272.13326332633463460.6980.030.36811.14490.79175.374.975.374.975.34.8574.9
2.504-2.7349.351.51371.42327432743503500.559-0.110.51691.6020.70431.532.631.516.115.24.9932.6

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROCdata processing
XDSjan 10, 2022data reduction
STARANISO2.3.77data scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: In house structure

Resolution: 2.504→73.03 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.944 / Cross valid method: THROUGHOUT / SU R Blow DPI: 3.057 / SU Rfree Blow DPI: 0.321
RfactorNum. reflection% reflectionSelection details
Rfree0.2395 363 -RANDOM
Rwork0.2052 ---
obs0.2069 7248 75.8 %-
Displacement parametersBiso mean: 77.83 Å2
Baniso -1Baniso -2Baniso -3
1-0.7349 Å20 Å20 Å2
2--0.7349 Å20 Å2
3----1.4697 Å2
Refine analyzeLuzzati coordinate error obs: 0.38 Å
Refinement stepCycle: LAST / Resolution: 2.504→73.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1761 0 23 26 1810
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0081824HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.932469HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d648SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes341HARMONIC5
X-RAY DIFFRACTIONt_it1813HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion240SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact1471SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.46
X-RAY DIFFRACTIONt_other_torsion20.42
LS refinement shellResolution: 2.504→2.74 Å
RfactorNum. reflection% reflection
Rfree0.2015 18 -
Rwork0.2832 --
obs--17.95 %

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