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- PDB-4fhh: Development of synthetically accessible non-secosteroidal hybrid ... -

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Basic information

Entry
Database: PDB / ID: 4fhh
TitleDevelopment of synthetically accessible non-secosteroidal hybrid molecules combining vitamin D receptor agonism and histone deacetylase inhibition
Components
  • Nuclear receptor coactivator 2
  • Vitamin D3 receptor A
KeywordsTranscription/protein binding/inhibitor / Ligand binding domain / apha helical sandwich / alpha helical sandwich / transcription factor / ADN Coregulators / phosphorylation and HDAC inhibitor / nucleus / Transcription-protein binding-inhibitor complex
Function / homology
Function and homology information


heart jogging / Vitamin D (calciferol) metabolism / : / SUMOylation of intracellular receptors / vitamin D binding / calcitriol binding / lithocholic acid binding / hematopoietic stem cell proliferation / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / heart looping ...heart jogging / Vitamin D (calciferol) metabolism / : / SUMOylation of intracellular receptors / vitamin D binding / calcitriol binding / lithocholic acid binding / hematopoietic stem cell proliferation / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / heart looping / 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 / calcium ion homeostasis / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Recycling of bile acids and salts / regulation of cellular response to insulin stimulus / cellular response to hormone stimulus / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / Regulation of lipid metabolism by PPARalpha / ossification / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / Activation of gene expression by SREBF (SREBP) / response to progesterone / nuclear receptor binding / circadian regulation of gene expression / 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 / RNA polymerase II transcription regulator complex / nuclear receptor activity / Circadian Clock / HATs acetylate histones / Estrogen-dependent gene expression / transcription regulator complex / cell differentiation / transcription coactivator activity / protein dimerization activity / nuclear body / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein domain specific binding / DNA-templated transcription / chromatin binding / chromatin / 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 / cytoplasm
Similarity search - Function
Vitamin D receptor / VDR, DNA-binding domain / 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 ...Vitamin D receptor / VDR, DNA-binding domain / 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 / 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-0U3 / Nuclear receptor coactivator 2 / Vitamin D3 receptor A
Similarity search - Component
Biological speciesDanio rerio (zebrafish)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.33 Å
AuthorsFischer, J. / Wang, T.T. / Kaldre, D. / Rochel, N. / Moras, D. / White, J.H. / Gleason, J.L.
CitationJournal: Chem.Biol. / Year: 2012
Title: Synthetically accessible non-secosteroidal hybrid molecules combining vitamin d receptor agonism and histone deacetylase inhibition.
Authors: Fischer, J. / Wang, T.T. / Kaldre, D. / Rochel, N. / Moras, D. / White, J.H. / Gleason, J.L.
History
DepositionJun 6, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 19, 2012Provider: repository / Type: Initial release
Revision 1.1Mar 10, 2021Group: Database references / Derived calculations
Category: pdbx_struct_assembly / pdbx_struct_assembly_gen ...pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list / struct_ref_seq_dif / struct_site
Item: _pdbx_struct_assembly.oligomeric_count / _pdbx_struct_assembly.oligomeric_details ..._pdbx_struct_assembly.oligomeric_count / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.oper_expression / _pdbx_struct_assembly_prop.value / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Vitamin D3 receptor A
B: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9543
Polymers35,4962
Non-polymers4581
Water1,820101
1
A: Vitamin D3 receptor A
B: Nuclear receptor coactivator 2
hetero molecules

A: Vitamin D3 receptor A
B: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,9086
Polymers70,9934
Non-polymers9152
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation10_665-y+1,-x+1,-z+1/61
Buried area3920 Å2
ΔGint-29 kcal/mol
Surface area21740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.289, 66.289, 264.225
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522

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Components

#1: Protein Vitamin D3 receptor A / VDR-A / 1 / 25-dihydroxyvitamin D3 receptor A / Nuclear receptor subfamily 1 group I member 1-A


Mass: 33916.543 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 156-453
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Danio rerio (zebrafish) / Gene: vdra, nr1i1a, vdr / Production host: Escherichia coli (E. coli) / References: UniProt: Q9PTN2
#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 / Fragment: UNP RESIDUES 686-698 / Source method: obtained synthetically / Details: This sequence occurs naturally in humans. / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596
#3: Chemical ChemComp-0U3 / N-hydroxy-2-{4-[3-(4-{[(2S)-2-hydroxy-3,3-dimethylbutyl]oxy}-3-methylphenyl)pentan-3-yl]-2-methylphenoxy}acetamide


Mass: 457.602 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H39NO5
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 101 / 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: 2.36 Å3/Da / Density % sol: 47.89 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: Bis Tris 0.1M, lithium sulfate 1.6M and magnesium sulfate 50 mM, VAPOR DIFFUSION, HANGING DROP, temperature 291K, pH 6.5

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.0723 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Nov 20, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0723 Å / Relative weight: 1
ReflectionResolution: 2.33→25 Å / Num. all: 15812 / Num. obs: 15812 / % possible obs: 100 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 2.33→2.41 Å / % possible all: 100

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Processing

Software
NameClassification
HKL-2000data collection
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.33→15 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.258 706 random
Rwork0.215 --
obs0.215 15230 -
all-15575 -
Refinement stepCycle: LAST / Resolution: 2.33→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1995 0 33 101 2129
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_angle_deg1.15
X-RAY DIFFRACTIONc_bond_d0.006

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