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- PDB-5a86: Structure of pregnane X receptor in complex with a Sphingosine 1-... -

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Basic information

Entry
Database: PDB / ID: 5a86
TitleStructure of pregnane X receptor in complex with a Sphingosine 1- Phosphate Receptor 1 Antagonist
Components
  • NUCLEAR RECEPTOR COACTIVATOR 1
  • NUCLEAR RECEPTOR SUBFAMILY 1 GROUP I MEMBER 2
KeywordsSIGNALING PROTEIN / PXR LIGAND / PXR AGONIST / CYP3A4 INDUCTION / NUCLEAR RECEPTOR
Function / homology
Function and homology information


xenobiotic transport / labyrinthine layer morphogenesis / regulation of thyroid hormone mediated signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of female receptivity / intermediate filament cytoskeleton / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / steroid metabolic process ...xenobiotic transport / labyrinthine layer morphogenesis / regulation of thyroid hormone mediated signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of female receptivity / intermediate filament cytoskeleton / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / steroid metabolic process / cellular response to Thyroglobulin triiodothyronine / estrous cycle / Synthesis of bile acids and bile salts / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / xenobiotic catabolic process / nuclear retinoid X receptor binding / response to retinoic acid / histone acetyltransferase activity / regulation of cellular response to insulin stimulus / Recycling of bile acids and salts / histone acetyltransferase / cellular response to hormone stimulus / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / lactation / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / xenobiotic metabolic process / cerebellum development / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / response to progesterone / nuclear estrogen receptor binding / hippocampus development / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Heme signaling / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / cerebral cortex development / 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 / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / transcription regulator complex / transcription coactivator activity / cell differentiation / nuclear body / protein dimerization activity / DNA-binding transcription factor activity, RNA polymerase II-specific / positive regulation of apoptotic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of DNA-templated transcription / chromatin binding / chromatin / regulation of DNA-templated transcription / positive regulation of gene expression / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / signal transduction / positive regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / nucleoplasm / nucleus / plasma membrane / cytosol
Similarity search - Function
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 ...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 DNA-binding domain superfamily / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily / 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-D7E / Nuclear receptor subfamily 1 group I member 2 / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsXue, Y. / Oster, L.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Identification and Optimization of Benzimidazole Sulfonamides as Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists with in Vivo Activity.
Authors: Hennessy, E.J. / Oza, V.B. / Adam, A. / Byth, K. / Castriotta, L. / Grewal, G. / Hamilton, G. / Kamhi, V.M. / Lewis, P. / Li, D. / Lyne, P.D. / Oster, L. / Rooney, M.T. / Saeh, J.C. / Sha, L. ...Authors: Hennessy, E.J. / Oza, V.B. / Adam, A. / Byth, K. / Castriotta, L. / Grewal, G. / Hamilton, G. / Kamhi, V.M. / Lewis, P. / Li, D. / Lyne, P.D. / Oster, L. / Rooney, M.T. / Saeh, J.C. / Sha, L. / Su, Q. / Wen, S. / Xue, Y. / Yang, B.
History
DepositionJul 13, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 21, 2015Provider: repository / Type: Initial release
Revision 1.1May 16, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_beamline
Revision 1.2May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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 I MEMBER 2
B: NUCLEAR RECEPTOR SUBFAMILY 1 GROUP I MEMBER 2
C: NUCLEAR RECEPTOR COACTIVATOR 1
D: NUCLEAR RECEPTOR COACTIVATOR 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,1826
Polymers76,3184
Non-polymers8642
Water5,423301
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4030 Å2
ΔGint-34.9 kcal/mol
Surface area28480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)83.670, 89.200, 106.560
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein NUCLEAR RECEPTOR SUBFAMILY 1 GROUP I MEMBER 2 / ORPHAN NUCLEAR RECEPTOR PAR1 / ORPHAN NUCLEAR RECEPTOR PXR / PREGNANE X RECEPTOR / STEROID AND ...ORPHAN NUCLEAR RECEPTOR PAR1 / ORPHAN NUCLEAR RECEPTOR PXR / PREGNANE X RECEPTOR / STEROID AND XENOBIOTIC RECEPTOR / SXR / STEROID RECEPTOR COACTIVATOR 1


Mass: 36136.738 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: O75469
#2: Protein/peptide NUCLEAR RECEPTOR COACTIVATOR 1 / / NCOA-1 / CLASS E BASIC HELIX-LOOP-HELIX PROTEIN 74 / BHLHE74 / PROTEIN HIN-2 / RIP160 / RENAL ...NCOA-1 / CLASS E BASIC HELIX-LOOP-HELIX PROTEIN 74 / BHLHE74 / PROTEIN HIN-2 / RIP160 / RENAL CARCINOMA ANTIGEN NY-REN-52 / STEROID RECEPTOR COACTIVATOR 1 / SRC-1 / STEROID RECEPTOR COACTIVATOR 1


Mass: 2022.333 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: Q15788, histone acetyltransferase
#3: Chemical ChemComp-D7E / 4-chloro-N-[(1R)-1-[1-ethyl-6-(trifluoromethyl)benzimidazol-2-yl]ethyl]benzenesulfonamide


Mass: 431.860 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H17ClF3N3O2S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 301 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.61 Å3/Da / Density % sol: 52.79 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Type: ESRF / Wavelength: 0.9395
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9395 Å / Relative weight: 1
ReflectionResolution: 2.25→45.74 Å / Num. obs: 37577 / % possible obs: 98 % / Observed criterion σ(I): 0 / Redundancy: 3.8 % / Biso Wilson estimate: 49.57 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 13.9
Reflection shellResolution: 2.25→2.31 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.55 / Mean I/σ(I) obs: 2.3 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.25→14.88 Å / Cor.coef. Fo:Fc: 0.9242 / Cor.coef. Fo:Fc free: 0.9175 / SU R Cruickshank DPI: 0.284 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.297 / SU Rfree Blow DPI: 0.215 / SU Rfree Cruickshank DPI: 0.213
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2555 1877 5.01 %RANDOM
Rwork0.2306 ---
obs0.2319 37467 97.62 %-
Displacement parametersBiso mean: 58.84 Å2
Baniso -1Baniso -2Baniso -3
1-0.6202 Å20 Å20 Å2
2---2.5639 Å20 Å2
3---1.9436 Å2
Refine analyzeLuzzati coordinate error obs: 0.356 Å
Refinement stepCycle: LAST / Resolution: 2.25→14.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4724 0 56 301 5081
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0084883HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.96578HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1759SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes121HARMONIC2
X-RAY DIFFRACTIONt_gen_planes687HARMONIC5
X-RAY DIFFRACTIONt_it4883HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.23
X-RAY DIFFRACTIONt_other_torsion19.3
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion613SEMIHARMONIC5
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_contact5950SEMIHARMONIC4
LS refinement shellResolution: 2.25→2.31 Å / Total num. of bins used: 19
RfactorNum. reflection% reflection
Rfree0.3353 152 5.1 %
Rwork0.3242 2826 -
all0.3248 2978 -
obs--99.97 %

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