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- PDB-6w9h: SUBSTITUTED BENZYLOXYTRICYCLIC COMPOUNDS AS RETINOIC ACID-RELATED... -

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Basic information

Entry
Database: PDB / ID: 6w9h
TitleSUBSTITUTED BENZYLOXYTRICYCLIC COMPOUNDS AS RETINOIC ACID-RELATED ORPHAN RECEPTOR GAMMA T AGONISTS
ComponentsNuclear receptor ROR-gamma, Steroid receptor coactivator 1 fusion
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / RORGT / NUCLEAR HORMONE RECEPTOR / LIGAND-BINDING DOMAIN / INVE 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-modulated transcription factor activity / Peyer's patch development / T-helper cell differentiation / positive regulation of circadian rhythm / RUNX3 Regulates Immune Response and Cell Migration / oxysterol binding / labyrinthine layer morphogenesis ...cellular response to sterol / T-helper 17 cell differentiation / regulation of steroid metabolic process / ligand-modulated transcription factor activity / Peyer's patch development / T-helper cell differentiation / positive regulation of circadian rhythm / RUNX3 Regulates Immune Response and Cell Migration / oxysterol binding / labyrinthine layer morphogenesis / negative regulation of thymocyte apoptotic process / positive regulation of transcription from RNA polymerase II promoter by galactose / regulation of thyroid hormone receptor signaling pathway / positive regulation of female receptivity / regulation of fat cell differentiation / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / hypothalamus development / male mating behavior / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Endogenous sterols / adipose tissue development / lymph node development / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear retinoid X receptor binding / response to retinoic acid / progesterone receptor signaling pathway / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / cellular response to hormone stimulus / histone H4K16 acetyltransferase activity / histone H3K56 acetyltransferase activity / histone H3K23 acetyltransferase activity / histone H2AK5 acetyltransferase activity / histone H2AK9 acetyltransferase activity / histone H2BK5 acetyltransferase activity / histone H2BK12 acetyltransferase activity / histone H3K4 acetyltransferase activity / histone H3K27 acetyltransferase activity / histone H3K36 acetyltransferase activity / histone H3K122 acetyltransferase activity / histone H3K18 acetyltransferase activity / histone H3K9 acetyltransferase activity / histone H3K14 acetyltransferase activity / histone H4K5 acetyltransferase activity / histone H4K8 acetyltransferase activity / histone H4K12 acetyltransferase activity / Recycling of bile acids and salts / histone acetyltransferase / estrous cycle / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / estrogen receptor signaling pathway / positive regulation of adipose tissue development / : / lactation / Regulation of lipid metabolism by PPARalpha / peroxisome proliferator activated receptor signaling pathway / regulation of cellular response to insulin stimulus / xenobiotic metabolic process / positive regulation of neuron differentiation / cerebellum development / BMAL1:CLOCK,NPAS2 activates circadian expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / hippocampus development / response to progesterone / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / nuclear estrogen receptor binding / circadian regulation of gene expression / mRNA transcription by RNA polymerase II / Heme signaling / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / cerebral cortex development / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / DNA-binding transcription repressor activity, RNA polymerase II-specific / RNA polymerase II transcription regulator complex / nuclear receptor activity / male gonad development / sequence-specific double-stranded DNA binding / : / response to estradiol / HATs acetylate histones / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / Interleukin-4 and Interleukin-13 signaling / transcription regulator complex / Estrogen-dependent gene expression / transcription coactivator activity / DNA-binding transcription factor activity, RNA polymerase II-specific / protein dimerization activity / nuclear body / positive regulation of apoptotic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / chromatin binding / regulation of transcription by RNA polymerase II
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 / Nuclear receptor coactivators bHLH domain / 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 / Double treble clef zinc finger, C4 type / 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-TKJ / Nuclear receptor ROR-gamma / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.995 Å
AuthorsSack, J.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Substituted benzyloxytricyclic compounds as retinoic acid-related orphan receptor gamma t (ROR gamma t) agonists.
Authors: Harikrishnan, L.S. / Gill, P. / Kamau, M.G. / Qin, L.Y. / Ruan, Z. / O'Malley, D. / Huynh, T. / Stachura, S. / Cavallaro, C.L. / Lu, Z. / J-W Duan, J. / Weigelt, C.A. / Sack, J.S. / Ruzanov, ...Authors: Harikrishnan, L.S. / Gill, P. / Kamau, M.G. / Qin, L.Y. / Ruan, Z. / O'Malley, D. / Huynh, T. / Stachura, S. / Cavallaro, C.L. / Lu, Z. / J-W Duan, J. / Weigelt, C.A. / Sack, J.S. / Ruzanov, M. / Khan, J. / Gururajan, M. / Wong, J.J. / Huang, Y. / Yarde, M. / Li, Z. / Chen, C. / Sun, H. / Borowski, V. / Murtaza, A. / Fink, B.E.
History
DepositionMar 23, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2020Provider: repository / Type: Initial release
Revision 1.1May 13, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Oct 18, 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: Nuclear receptor ROR-gamma, Steroid receptor coactivator 1 fusion
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4592
Polymers32,8871
Non-polymers5721
Water2,414134
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.729, 61.729, 155.778
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Nuclear receptor ROR-gamma, Steroid receptor coactivator 1 fusion / 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 / SRC-1


Mass: 32886.922 Da / Num. of mol.: 1
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-TKJ / 4-{(3R)-3-[4-(benzyloxy)phenyl]-3-[(4-fluorophenyl)sulfonyl]pyrrolidine-1-carbonyl}-1lambda~6~-thiane-1,1-dione


Mass: 571.680 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C29H30FNO6S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 134 / 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: 295 K / Method: vapor diffusion, hanging drop
Details: protein at 8-10mg/ml, with 0.2M MgCl2, 22% PEG3350, 0.1M Bis-Tris pH 5.5

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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: Dec 16, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.995→57.39 Å / Num. obs: 15332 / % possible obs: 71.9 % / Redundancy: 12.3 % / Biso Wilson estimate: 31.01 Å2 / Rmerge(I) obs: 0.159 / Net I/σ(I): 12.7
Reflection shellResolution: 2→2.15 Å / Redundancy: 10.9 % / Rmerge(I) obs: 1.945 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 1000 / % possible all: 18.1

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (6-FEB-2020)refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6vqf

6vqf


Resolution: 1.995→57.39 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.874 / SU R Cruickshank DPI: 0.257 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.284 / SU Rfree Blow DPI: 0.224 / SU Rfree Cruickshank DPI: 0.217
RfactorNum. reflection% reflectionSelection details
Rfree0.2579 785 5.12 %RANDOM
Rwork0.1982 ---
obs0.2014 15332 71.8 %-
Displacement parametersBiso max: 83.85 Å2 / Biso mean: 31.78 Å2 / Biso min: 15.43 Å2
Baniso -1Baniso -2Baniso -3
1--0.5391 Å20 Å20 Å2
2---0.5391 Å20 Å2
3---1.0782 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 1.995→57.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2038 0 39 134 2211
Biso mean--50.29 37.95 -
Num. residues----253
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d762SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes377HARMONIC5
X-RAY DIFFRACTIONt_it2123HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
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_contact1794SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2123HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg2868HARMONIC20.89
X-RAY DIFFRACTIONt_omega_torsion2.58
X-RAY DIFFRACTIONt_other_torsion16.84
LS refinement shellResolution: 2→2.1 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.2927 23 5.84 %
Rwork0.2007 371 -
obs--20 %

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