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- PDB-4m8e: CRYSTAL STRUCTURE OF HUMAN RETINOID X RECEPTOR ALPHA-LIGAND BINDI... -

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Entry
Database: PDB / ID: 4m8e
TitleCRYSTAL STRUCTURE OF HUMAN RETINOID X RECEPTOR ALPHA-LIGAND BINDING DOMAIN COMPLEX WITH (S) 4-Methyl 9cUAB30 COACTIVATOR PEPTIDE GRIP-1
Components
  • Nuclear receptor coactivator 2
  • Retinoic acid receptor RXR-alpha
KeywordsTRANSCRIPTION / ANTIPARALLEL SANDWICH / LIGAND BINDING / COACTIVATOR BINDING / DIMERIZATION / ACTIVATION FUNCTION / nuclear receptors / ligand binding domian / ligand binding pocket / coactivator binding site / cancer / 4-Methyl 9cUAB30 ((2E / 4E / 6Z / 8E)-8-[(4'S)methyl-3' / 4'-dihydro-1'(2'H)-naphthalen-1'-ylidene]-3 / 7-dimethyl-2 / 4 / 6-octatrienoic Acid)
Function / homology
Function and homology information


positive regulation of transporter activity / retinoic acid-responsive element binding / NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis / NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose / NR1H2 & NR1H3 regulate gene expression to limit cholesterol uptake / positive regulation of thyroid hormone receptor signaling pathway / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / Carnitine metabolism / ion binding / Regulation of pyruvate dehydrogenase (PDH) complex ...positive regulation of transporter activity / retinoic acid-responsive element binding / NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis / NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose / NR1H2 & NR1H3 regulate gene expression to limit cholesterol uptake / positive regulation of thyroid hormone receptor signaling pathway / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / Carnitine metabolism / ion binding / Regulation of pyruvate dehydrogenase (PDH) complex / retinoic acid binding / positive regulation of vitamin D receptor signaling pathway / nuclear vitamin D receptor binding / Signaling by Retinoic Acid / DNA binding domain binding / nuclear steroid receptor activity / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / LBD domain binding / locomotor rhythm / aryl hydrocarbon receptor binding / regulation of lipid metabolic process / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / positive regulation of cholesterol efflux / retinoic acid receptor signaling pathway / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / positive regulation of bone mineralization / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / response to retinoic acid / regulation of cellular response to insulin stimulus / Recycling of bile acids and salts / 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 / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / transcription coregulator binding / response to progesterone / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / peptide binding / circadian regulation of gene expression / Heme signaling / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / Transcriptional regulation of white adipocyte differentiation / Activation of anterior HOX genes in hindbrain development during early embryogenesis / Nuclear Receptor transcription pathway / Transcriptional regulation of granulopoiesis / RNA polymerase II transcription regulator complex / nuclear receptor activity / sequence-specific double-stranded DNA binding / Circadian Clock / HATs acetylate histones / double-stranded DNA binding / Estrogen-dependent gene expression / transcription regulator complex / sequence-specific DNA binding / transcription coactivator activity / cell differentiation / receptor complex / nuclear body / protein dimerization activity / transcription cis-regulatory region binding / DNA-binding transcription factor activity, RNA polymerase II-specific / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein domain specific binding / chromatin binding / regulation of DNA-templated transcription / chromatin / positive regulation of DNA-templated transcription / enzyme binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / zinc ion binding / nucleoplasm / identical protein binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Nuclear/hormone receptor activator site AF-1 / Nuclear/hormone receptor activator site AF-1 / Retinoid X receptor/HNF4 / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 ...Nuclear/hormone receptor activator site AF-1 / Nuclear/hormone receptor activator site AF-1 / Retinoid X receptor/HNF4 / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / 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 / 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-29V / Retinoic acid receptor RXR-alpha / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.4 Å
AuthorsXia, G. / Smith, C.D. / Muccio, D.D.
CitationJournal: Bioorg.Med.Chem. / Year: 2014
Title: Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention.
Authors: Desphande, A. / Xia, G. / Boerma, L.J. / Vines, K.K. / Atigadda, V.R. / Lobo-Ruppert, S. / Grubbs, C.J. / Moeinpour, F.L. / Smith, C.D. / Christov, K. / Brouillette, W.J. / Muccio, D.D.
History
DepositionAug 13, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 17, 2019Group: Data collection / Refinement description / Category: software
Item: _software.contact_author / _software.contact_author_email ..._software.contact_author / _software.contact_author_email / _software.language / _software.location / _software.name / _software.type
Revision 1.2Aug 17, 2022Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_assembly ...database_2 / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_assembly.details / _pdbx_struct_assembly.method_details / _pdbx_struct_assembly.oligomeric_count / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.oper_expression / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Feb 28, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Retinoic acid receptor RXR-alpha
B: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,6133
Polymers27,3032
Non-polymers3101
Water2,342130
1
A: Retinoic acid receptor RXR-alpha
B: Nuclear receptor coactivator 2
hetero molecules

A: Retinoic acid receptor RXR-alpha
B: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,2266
Polymers54,6054
Non-polymers6212
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_775-y+2,-x+2,-z+1/21
Unit cell
Length a, b, c (Å)66.279, 66.279, 111.011
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein Retinoic acid receptor RXR-alpha / Nuclear receptor subfamily 2 group B member 1 / Retinoid X receptor alpha


Mass: 25897.021 Da / Num. of mol.: 1 / Fragment: HRXRALPHA-LBD, UNP RESIDUES 228-458
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Strain: P19793 / Gene: NR2B1, RXRA / Production host: Escherichia coli (E. coli) / References: UniProt: P19793
#2: Protein/peptide Nuclear receptor coactivator 2 / NCoA-2 / Class E basic helix-loop-helix protein 75 / bHLHe75 / Transcriptional intermediary factor 2 / hTIF2


Mass: 1405.710 Da / Num. of mol.: 1 / Fragment: GRIP-1, UNP RESIDUES 686-696 / Source method: obtained synthetically / Details: GRIP-1 from AnaSpec Inc / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596
#3: Chemical ChemComp-29V / (3E,6Z,8E)-3,7-dimethyl-8-[(4S)-4-methyl-3,4-dihydronaphthalen-1(2H)-ylidene]octa-3,6-dienoic acid


Mass: 310.430 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H26O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 130 / 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: 2.26 Å3/Da / Density % sol: 45.7 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 4-20% PEG4000, 4-16% GLYCEROL, 0.1M BIS-TRIS, PH7.0, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Site: APS / Beamline: 22-ID / Type: OTHER / Wavelength: 1.5418 / Wavelength: 1.315 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Feb 19, 2009
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
11.54181
21.3151
ReflectionResolution: 2.4→26.15 Å / % possible obs: 98.7 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 10.28 % / Rmerge(I) obs: 0.076 / Rsym value: 0.314 / Net I/σ(I): 17
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 10.03 % / Mean I/σ(I) obs: 6.5 / Num. unique all: 979 / Rsym value: 0.314 / % possible all: 99.3

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Processing

Software
NameVersionClassificationNB
CNSrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
REFMACrefinement
RefinementResolution: 2.4→26.15 Å / Occupancy max: 1 / Occupancy min: 1 / σ(F): 0
RfactorNum. reflection% reflection
Rfree0.2468 1734 9.4 %
Rwork0.2085 16530 -
obs-18264 98.9 %
Solvent computationBsol: 42.2483 Å2
Displacement parametersBiso max: 81.98 Å2 / Biso mean: 40.0006 Å2 / Biso min: 0 Å2
Baniso -1Baniso -2Baniso -3
1-4.135 Å20 Å20 Å2
2--4.135 Å20 Å2
3----8.27 Å2
Refinement stepCycle: LAST / Resolution: 2.4→26.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1785 0 23 130 1938
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_d1.091
X-RAY DIFFRACTIONc_mcbond_it1.3841.5
X-RAY DIFFRACTIONc_scbond_it1.8312
X-RAY DIFFRACTIONc_mcangle_it2.352
X-RAY DIFFRACTIONc_scangle_it2.7122.5
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1CNS_TOPPAR:protein_rep.paramCNS_TOPPAR:protein.top
X-RAY DIFFRACTION2modify-4mUAB30.parmodify-4mUAB30.top
X-RAY DIFFRACTION3CNS_TOPPAR:water_rep.paramCNS_TOPPAR:water.top

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