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- PDB-6u25: CRYSTAL STRUCTURE OF RAR-RELATED ORPHAN RECEPTOR C (NHIS- RORGT(2... -

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Basic information

Entry
Database: PDB / ID: 6u25
TitleCRYSTAL STRUCTURE OF RAR-RELATED ORPHAN RECEPTOR C (NHIS- RORGT(244-487)-L6-SRC1(678-692)) IN COMPLEX WITH A TRICYCLIC INVERSE AGONIST
ComponentsNUCLEAR RECEPTOR COACTIVATOR 1 CHIMERA
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / RORGT / NUCLEAR HORMONE RECEPTOR / LIGAND-BINDING DOMAIN / INVERSE AGONIST / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX / TRANSFERASE
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 / labyrinthine layer morphogenesis ...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 / labyrinthine layer morphogenesis / negative regulation of thymocyte apoptotic process / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of female receptivity / regulation of fat cell differentiation / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / estrous cycle / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / lymph node development / adipose tissue development / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / progesterone receptor signaling pathway / nuclear retinoid X receptor binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / response to retinoic acid / histone acetyltransferase activity / Recycling of bile acids and salts / histone acetyltransferase / cellular response to hormone stimulus / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / estrogen receptor signaling pathway / positive regulation of adipose tissue development / RORA activates gene expression / peroxisome proliferator activated receptor signaling pathway / lactation / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / xenobiotic metabolic process / regulation of cellular response to insulin stimulus / cerebellum development / BMAL1:CLOCK,NPAS2 activates circadian gene expression / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / response to progesterone / nuclear receptor binding / nuclear estrogen receptor binding / hippocampus development / RNA polymerase II transcription regulatory region sequence-specific DNA binding / circadian regulation of gene expression / Heme signaling / mRNA transcription by RNA polymerase II / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / cerebral cortex development / DNA-binding transcription repressor activity, RNA polymerase II-specific / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / nuclear receptor activity / male gonad development / sequence-specific double-stranded DNA binding / Circadian Clock / response to estradiol / HATs acetylate histones / Interleukin-4 and Interleukin-13 signaling / Estrogen-dependent gene expression / transcription regulator complex / transcription coactivator activity / protein dimerization activity / DNA-binding transcription factor activity, RNA polymerase II-specific / nuclear body / positive regulation of apoptotic process / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / chromatin binding / chromatin / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / nucleoplasm / nucleus / plasma membrane / cytosol
Similarity search - Function
Nuclear receptor ROR / Retinoid-related orphan receptors, DNA-binding domain / Nuclear receptor coactivator 1 / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain ...Nuclear receptor ROR / Retinoid-related orphan receptors, DNA-binding domain / Nuclear receptor coactivator 1 / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain / Nuclear receptor coactivator / Steroid receptor coactivator / Unstructured region on nuclear receptor coactivator protein / PAS domain / Nuclear receptor coactivator, interlocking / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Helix-loop-helix DNA-binding domain superfamily / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / Retinoid X Receptor / Retinoid X Receptor / PAS 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-O5B / Nuclear receptor ROR-gamma / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å
AuthorsSack, J.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Rationally Designed, Conformationally Constrained Inverse Agonists of ROR gamma t-Identification of a Potent, Selective Series with Biologic-Like in Vivo Efficacy.
Authors: Marcoux, D. / Duan, J.J. / Shi, Q. / Cherney, R.J. / Srivastava, A.S. / Cornelius, L. / Batt, D.G. / Liu, Q. / Beaudoin-Bertrand, M. / Weigelt, C.A. / Khandelwal, P. / Vishwakrishnan, S. / ...Authors: Marcoux, D. / Duan, J.J. / Shi, Q. / Cherney, R.J. / Srivastava, A.S. / Cornelius, L. / Batt, D.G. / Liu, Q. / Beaudoin-Bertrand, M. / Weigelt, C.A. / Khandelwal, P. / Vishwakrishnan, S. / Selvakumar, K. / Karmakar, A. / Gupta, A.K. / Basha, M. / Ramlingam, S. / Manjunath, N. / Vanteru, S. / Karmakar, S. / Maddala, N. / Vetrichelvan, M. / Gupta, A. / Rampulla, R.A. / Mathur, A. / Yip, S. / Li, P. / Wu, D.R. / Khan, J. / Ruzanov, M. / Sack, J.S. / Wang, J. / Yarde, M. / Cvijic, M.E. / Li, S. / Shuster, D.J. / Borowski, V. / Xie, J.H. / McIntyre, K.W. / Obermeier, M.T. / Fura, A. / Stefanski, K. / Cornelius, G. / Hynes Jr., J. / Tino, J.A. / Macor, J.E. / Salter-Cid, L. / Denton, R. / Zhao, Q. / Carter, P.H. / Dhar, T.G.M.
History
DepositionAug 19, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 6, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2019Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Nov 27, 2019Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 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 / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: NUCLEAR RECEPTOR COACTIVATOR 1 CHIMERA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6333
Polymers32,8871
Non-polymers7462
Water1086
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)61.656, 61.656, 158.271
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein NUCLEAR RECEPTOR COACTIVATOR 1 CHIMERA / Nuclear receptor RZR-gamma / Steroid receptor coactivator 1 / SRC-1


Mass: 32886.922 Da / Num. of mol.: 1
Fragment: LIGAND-BINDING DOMAIN (UNP RESIDUES 265-508) FUSED TO SRC PEPTIDE (UNP RESIDUES 683-696)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RORC, NR1F3, RORG, RZRG, NCOA1, BHLHE74, SRC1 / Production host: Escherichia coli (E. coli)
References: UniProt: P51449, UniProt: Q15788, histone acetyltransferase
#2: Chemical ChemComp-O5B / trans-4-[(3aR,9bR)-9b-[(4-fluorophenyl)sulfonyl]-7-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carbonyl]cyclohexane-1-carboxylic acid


Mass: 653.581 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H27F8NO5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / 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: 2.29 Å3/Da / Density % sol: 46.21 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 20-26% PEG3350, 0.2 M MAGNESIUM CHLORIDE, 0.1 M BIS-TRIS PH 5.5-6.5
PH range: 5.5-6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 18, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.61→158.27 Å / Num. obs: 9969 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 12.5 % / Biso Wilson estimate: 70.78 Å2 / Rmerge(I) obs: 0.112 / Net I/σ(I): 18.6
Reflection shellResolution: 2.61→3.69 Å / Redundancy: 12.9 % / Rmerge(I) obs: 0.32 / Mean I/σ(I) obs: 7.8 / Num. unique obs: 6288 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
autoPROCdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6pf9

6pf9


Resolution: 2.61→48.64 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.91 / SU R Cruickshank DPI: 0.629 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.729 / SU Rfree Blow DPI: 0.297 / SU Rfree Cruickshank DPI: 0.295
RfactorNum. reflection% reflectionSelection details
Rfree0.247 508 5.12 %RANDOM
Rwork0.206 ---
obs0.208 9913 100 %-
Displacement parametersBiso mean: 58.1 Å2
Baniso -1Baniso -2Baniso -3
1--4.0924 Å20 Å20 Å2
2---4.0924 Å20 Å2
3---8.1848 Å2
Refine analyzeLuzzati coordinate error obs: 0.35 Å
Refinement stepCycle: LAST / Resolution: 2.61→48.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2043 0 50 6 2099
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012137HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.092889HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d776SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes371HARMONIC5
X-RAY DIFFRACTIONt_it2137HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.6
X-RAY DIFFRACTIONt_other_torsion17.38
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion264SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2428SEMIHARMONIC4
LS refinement shellResolution: 2.61→3.69 Å
RfactorNum. reflection% reflection
Rfree0.3132 -6.05 %
Rwork0.2366 373 -
obs--100 %

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