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- PDB-6k5o: Development of Novel Lithocholic Acid Derivatives as Vitamin D Re... -

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Basic information

Entry
Database: PDB / ID: 6k5o
TitleDevelopment of Novel Lithocholic Acid Derivatives as Vitamin D Receptor Agonists
Components
  • Mediator of RNA polymerase II transcription subunit 1
  • Vitamin D3 receptor
KeywordsTRANSCRIPTION / VITAMIN D RECEPTOR
Function / homology
Function and homology information


enucleate erythrocyte development / positive regulation of type II interferon-mediated signaling pathway / mammary gland branching involved in thelarche / negative regulation of bone trabecula formation / Vitamin D (calciferol) metabolism / regulation of RNA biosynthetic process / androgen biosynthetic process / positive regulation of G0 to G1 transition / retinal pigment epithelium development / G0 to G1 transition ...enucleate erythrocyte development / positive regulation of type II interferon-mediated signaling pathway / mammary gland branching involved in thelarche / negative regulation of bone trabecula formation / Vitamin D (calciferol) metabolism / regulation of RNA biosynthetic process / androgen biosynthetic process / positive regulation of G0 to G1 transition / retinal pigment epithelium development / G0 to G1 transition / dense fibrillar component / SUMOylation of intracellular receptors / thyroid hormone mediated signaling pathway / Nuclear Receptor transcription pathway / bile acid nuclear receptor activity / response to bile acid / core mediator complex / regulation of vitamin D receptor signaling pathway / positive regulation of parathyroid hormone secretion / phosphate ion transmembrane transport / apoptotic process involved in mammary gland involution / vitamin D binding / cellular response to vitamin D / positive regulation of apoptotic process involved in mammary gland involution / calcitriol binding / lithocholic acid binding / mediator complex / nuclear retinoic acid receptor binding / ventricular trabecula myocardium morphogenesis / thyroid hormone generation / positive regulation of keratinocyte differentiation / Generic Transcription Pathway / embryonic heart tube development / negative regulation of ossification / positive regulation of hepatocyte proliferation / cellular response to thyroid hormone stimulus / positive regulation of vitamin D receptor signaling pathway / embryonic hindlimb morphogenesis / peroxisome proliferator activated receptor binding / nuclear vitamin D receptor binding / vitamin D receptor signaling pathway / bile acid signaling pathway / intestinal absorption / lens development in camera-type eye / nuclear thyroid hormone receptor binding / embryonic hemopoiesis / positive regulation of intracellular estrogen receptor signaling pathway / histone acetyltransferase binding / megakaryocyte development / erythrocyte development / response to aldosterone / cellular response to hepatocyte growth factor stimulus / cellular response to steroid hormone stimulus / epithelial cell proliferation involved in mammary gland duct elongation / LBD domain binding / fat cell differentiation / mammary gland branching involved in pregnancy / monocyte differentiation / regulation of calcium ion transport / decidualization / general transcription initiation factor binding / negative regulation of neuron differentiation / positive regulation of transcription initiation by RNA polymerase II / hematopoietic stem cell differentiation / embryonic placenta development / negative regulation of keratinocyte proliferation / animal organ regeneration / heterochromatin / ubiquitin ligase complex / nuclear retinoid X receptor binding / intracellular steroid hormone receptor signaling pathway / RNA polymerase II preinitiation complex assembly / keratinocyte differentiation / cellular response to epidermal growth factor stimulus / T-tubule / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / lactation / Regulation of lipid metabolism by PPARalpha / BMAL1:CLOCK,NPAS2 activates circadian gene expression / nuclear receptor coactivator activity / Activation of gene expression by SREBF (SREBP) / positive regulation of erythrocyte differentiation / liver development / skeletal system development / nuclear estrogen receptor binding / promoter-specific chromatin binding / apoptotic signaling pathway / nuclear receptor binding / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / animal organ morphogenesis / brain development / euchromatin / Heme signaling / mRNA transcription by RNA polymerase II / cell morphogenesis / Transcriptional activation of mitochondrial biogenesis / transcription coactivator binding / intracellular calcium ion homeostasis
Similarity search - Function
Mediator complex, subunit Med1 / Mediator of RNA polymerase II transcription subunit 1 / Vitamin D receptor / VDR, DNA-binding domain / 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) ...Mediator complex, subunit Med1 / Mediator of RNA polymerase II transcription subunit 1 / Vitamin D receptor / VDR, DNA-binding domain / 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-D0O / Vitamin D3 receptor / Mediator of RNA polymerase II transcription subunit 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsMasuno, H. / Kagechika, H. / Ito, N.
Funding support Japan, 3items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science15K08018 Japan
Japan Society for the Promotion of Science16K08318 Japan
Japan Society for the Promotion of Science17H03997 Japan
CitationJournal: Bioorg.Med.Chem. / Year: 2019
Title: Development of novel lithocholic acid derivatives as vitamin D receptor agonists.
Authors: Masuno, H. / Kazui, Y. / Tanatani, A. / Fujii, S. / Kawachi, E. / Ikura, T. / Ito, N. / Yamamoto, K. / Kagechika, H.
History
DepositionMay 29, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 24, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 14, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Nov 22, 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: Vitamin D3 receptor
C: Mediator of RNA polymerase II transcription subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6213
Polymers32,1662
Non-polymers4551
Water46826
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1020 Å2
ΔGint-9 kcal/mol
Surface area11590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)153.884, 43.690, 41.792
Angle α, β, γ (deg.)90.00, 96.05, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 30595.037 Da / Num. of mol.: 1 / Mutation: 165-211 deletion
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Vdr, Nr1i1 / Production host: Escherichia coli (E. coli) / References: UniProt: P13053
#2: Protein/peptide Mediator of RNA polymerase II transcription subunit 1 / Activator-recruited cofactor 205 kDa component / ARC205 / Mediator complex subunit 1 / Peroxisome ...Activator-recruited cofactor 205 kDa component / ARC205 / Mediator complex subunit 1 / Peroxisome proliferator-activated receptor-binding protein / PPAR-binding protein / Thyroid hormone receptor-associated protein complex 220 kDa component / Trap220 / Thyroid receptor-interacting protein 2 / TRIP-2 / Vitamin D receptor-interacting protein complex component DRIP205 / p53 regulatory protein RB18A


Mass: 1570.898 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15648
#3: Chemical ChemComp-D0O / (4~{R})-4-[(3~{R},5~{R},8~{R},9~{S},10~{S},13~{R},14~{S},17~{R})-10,13-dimethyl-3-methylsulfonyloxy-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1~{H}-cyclopenta[a]phenanthren-17-yl]pentanoic acid


Mass: 454.663 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H42O5S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 26 / 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: 2.17 Å3/Da / Density % sol: 43.36 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.1M MOPS/NaOH (pH 7.0), 0.1-0.4 M sodium formate, 12-22% (w/v) PEG4000, and 5% (v/v) ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-6A / Wavelength: 0.978 Å
DetectorType: ADSC QUANTUM 4r / Detector: CCD / Date: Jun 12, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 25497 / % possible obs: 98.6 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.043 / Net I/σ(I): 16.3
Reflection shellResolution: 1.8→1.83 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.76 / Mean I/σ(I) obs: 1.28 / Num. unique obs: 1198 / CC1/2: 0.796 / % possible all: 91.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0222refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2ZLC

2zlc


Resolution: 1.8→35.01 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.949 / SU B: 6.727 / SU ML: 0.172 / Cross valid method: THROUGHOUT / ESU R: 0.138 / ESU R Free: 0.137 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25672 1214 4.8 %RANDOM
Rwork0.21116 ---
obs0.21324 24273 98.37 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 41.527 Å2
Baniso -1Baniso -2Baniso -3
1--4.19 Å20 Å2-0.97 Å2
2--6.32 Å20 Å2
3----1.88 Å2
Refinement stepCycle: 1 / Resolution: 1.8→35.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1984 0 31 26 2041
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0142059
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171916
X-RAY DIFFRACTIONr_angle_refined_deg1.4061.6762789
X-RAY DIFFRACTIONr_angle_other_deg0.9281.6624510
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.685244
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.56422.941102
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.9115378
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.0331511
X-RAY DIFFRACTIONr_chiral_restr0.070.2274
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022203
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02341
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.9574.071985
X-RAY DIFFRACTIONr_mcbond_other2.944.07984
X-RAY DIFFRACTIONr_mcangle_it4.1736.0851226
X-RAY DIFFRACTIONr_mcangle_other4.1756.0871227
X-RAY DIFFRACTIONr_scbond_it3.5964.4471074
X-RAY DIFFRACTIONr_scbond_other3.5954.4481075
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.4736.5051564
X-RAY DIFFRACTIONr_long_range_B_refined6.39147.9832299
X-RAY DIFFRACTIONr_long_range_B_other6.39647.9852300
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.799→1.845 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.423 88 -
Rwork0.384 1593 -
obs--89.89 %

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