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- PDB-7uw2: Crystal structure of human Retinoid X receptor alpha ligand bindi... -

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Basic information

Entry
Database: PDB / ID: 7uw2
TitleCrystal structure of human Retinoid X receptor alpha ligand binding domain complex with UAB116 and coactivator peptide GRIP-1
Components
  • Nuclear receptor coactivator 2
  • Retinoic acid receptor RXR-alpha
KeywordsTRANSCRIPTION / Retinoid X Receptor / Retinoid X Receptor alpha / ligand binding domain / Coactivator complex / Inhibitor complex
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 shuttle / retinoic acid binding / TGFBR3 expression ...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 shuttle / retinoic acid binding / TGFBR3 expression / 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 / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / positive regulation of bone mineralization / retinoic acid receptor signaling pathway / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / response to retinoic acid / 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 / RORA activates gene expression / peroxisome proliferator activated receptor signaling pathway / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / regulation of cellular response to insulin stimulus / 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 / circadian regulation of gene expression / peptide binding / SUMOylation of intracellular receptors / Heme signaling / 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 / Nuclear Receptor transcription pathway / Activation of anterior HOX genes in hindbrain development during early embryogenesis / 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 / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein domain specific binding / chromatin binding / regulation of DNA-templated transcription / chromatin / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / enzyme binding / positive regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / zinc ion binding / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
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/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 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 / 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
Similarity search - Domain/homology
Chem-OI2 / Retinoic acid receptor RXR-alpha / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.88 Å
AuthorsChattopadhyay, D. / Yang, Z. / Atigadda, V.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5P01CA210946 United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Conformationally Defined Rexinoids for the Prevention of Inflammation and Nonmelanoma Skin Cancers.
Authors: Atigadda, V.R. / Kashyap, M.P. / Yang, Z. / Chattopadhyay, D. / Melo, N. / Sinha, R. / Belyaeva, O.V. / Chou, C.F. / Chang, P.L. / Kedishvili, N.Y. / Grubbs, C.J. / Renfrow, M.B. / Muccio, D. ...Authors: Atigadda, V.R. / Kashyap, M.P. / Yang, Z. / Chattopadhyay, D. / Melo, N. / Sinha, R. / Belyaeva, O.V. / Chou, C.F. / Chang, P.L. / Kedishvili, N.Y. / Grubbs, C.J. / Renfrow, M.B. / Muccio, D.D. / Elmets, C.A. / Athar, M.
History
DepositionMay 2, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 15, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: 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

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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)28,8063
Polymers28,4362
Non-polymers3711
Water1,838102
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1090 Å2
ΔGint-9 kcal/mol
Surface area10600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.814, 65.814, 112.921
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Space group name HallP4nw2abw

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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: 26856.039 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RXRA, NR2B1 / 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: 1579.866 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596
#3: Chemical ChemComp-OI2 / (2E,4E,6Z,8E)-8-{3-[(2S)-butan-2-yl]-2-(3-methylbutyl)cyclohex-2-en-1-ylidene}-3,7-dimethylocta-2,4,6-trienoic acid


Mass: 370.568 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H38O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 102 / 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: 2.88 Å3/Da / Density % sol: 57.3 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 100 mM Bis-Tris, pH 7.0, 8% PEG4000, 25% ethylene glycol. The drop contained 2 ul protein + 1 ul well solution

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 1, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.88→65.81 Å / Num. obs: 20938 / % possible obs: 100 % / Redundancy: 14.5 % / Biso Wilson estimate: 39.03 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.056 / Rpim(I) all: 0.015 / Rrim(I) all: 0.058 / Net I/σ(I): 26.5 / Num. measured all: 303462 / Scaling rejects: 7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.88-1.9215.30.6522009013110.9690.170.6745100
9.02-65.8110.70.0526982510.9990.0140.05246.399.4

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHENIX1.19.2_4158phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4k4j

4k4j


Resolution: 1.88→43.03 Å / SU ML: 0.1743 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 25.2645
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2181 1036 4.96 %
Rwork0.2028 19831 -
obs0.2036 20867 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 42.8 Å2
Refinement stepCycle: LAST / Resolution: 1.88→43.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1747 0 27 102 1876
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0021816
X-RAY DIFFRACTIONf_angle_d0.60112452
X-RAY DIFFRACTIONf_chiral_restr0.0395280
X-RAY DIFFRACTIONf_plane_restr0.0043311
X-RAY DIFFRACTIONf_dihedral_angle_d14.9611251
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.88-1.980.30621420.23952772X-RAY DIFFRACTION99.9
1.98-2.10.27241420.2362768X-RAY DIFFRACTION99.76
2.1-2.270.2741440.22252793X-RAY DIFFRACTION99.93
2.27-2.490.2761360.21762806X-RAY DIFFRACTION100
2.49-2.850.26391720.22742800X-RAY DIFFRACTION99.77
2.85-3.60.22171460.21332862X-RAY DIFFRACTION100
3.6-43.030.17631540.18023030X-RAY DIFFRACTION99.78

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