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- PDB-1pcg: Helix-stabilized cyclic peptides as selective inhibitors of stero... -

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Basic information

Entry
Database: PDB / ID: 1pcg
TitleHelix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions
Components
  • estrogen receptor
  • peptide inhibitor
KeywordsTRANSCRIPTION/INHIBITOR / co-activator binding site / TRANSCRIPTION-INHIBITOR COMPLEX
Function / homology
Function and homology information


regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / regulation of branching involved in prostate gland morphogenesis / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / regulation of toll-like receptor signaling pathway / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / nuclear estrogen receptor activity / epithelial cell proliferation involved in mammary gland duct elongation ...regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / regulation of branching involved in prostate gland morphogenesis / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / regulation of toll-like receptor signaling pathway / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / nuclear estrogen receptor activity / epithelial cell proliferation involved in mammary gland duct elongation / prostate epithelial cord elongation / epithelial cell development / negative regulation of smooth muscle cell apoptotic process / mammary gland branching involved in pregnancy / uterus development / vagina development / androgen metabolic process / TFIIB-class transcription factor binding / steroid hormone mediated signaling pathway / mammary gland alveolus development / intracellular estrogen receptor signaling pathway / cellular response to estrogen stimulus / estrogen response element binding / positive regulation of phospholipase C activity / intracellular steroid hormone receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / protein localization to chromatin / TBP-class protein binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / steroid binding / nitric-oxide synthase regulator activity / ESR-mediated signaling / 14-3-3 protein binding / transcription corepressor binding / negative regulation of miRNA transcription / cellular response to estradiol stimulus / nuclear estrogen receptor binding / transcription coregulator binding / stem cell differentiation / positive regulation of nitric-oxide synthase activity / euchromatin / SUMOylation of intracellular receptors / negative regulation of DNA-binding transcription factor activity / transcription coactivator binding / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / male gonad development / Regulation of RUNX2 expression and activity / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of nitric oxide biosynthetic process / nuclear receptor activity / positive regulation of DNA-binding transcription factor activity / positive regulation of fibroblast proliferation / Ovarian tumor domain proteases / sequence-specific double-stranded DNA binding / response to estradiol / PIP3 activates AKT signaling / phospholipase C-activating G protein-coupled receptor signaling pathway / ATPase binding / positive regulation of cytosolic calcium ion concentration / fibroblast proliferation / regulation of inflammatory response / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / transcription regulator complex / Extra-nuclear estrogen signaling / calmodulin binding / DNA-binding transcription factor activity, RNA polymerase II-specific / chromatin remodeling / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of gene expression / chromatin binding / chromatin / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / protein kinase binding / positive regulation of DNA-templated transcription / Golgi apparatus / negative regulation of transcription by RNA polymerase II / enzyme binding / signal transduction / positive regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / nucleoplasm / membrane / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Estrogen receptor / Oestrogen-type nuclear receptor final C-terminal domain / : / Oestrogen receptor / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor/oestrogen-related receptor / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. ...Estrogen receptor / Oestrogen-type nuclear receptor final C-terminal domain / : / Oestrogen receptor / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor/oestrogen-related receptor / 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
ESTRADIOL / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsLeduc, A.M. / Trent, J.O. / Wittliff, J.L. / Bramlett, K.S. / Briggs, S.L. / Chirgadze, N.Y. / Wang, Y. / Burris, T.P. / Spatola, A.F.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2003
Title: Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions
Authors: Leduc, A.M. / Trent, J.O. / Wittliff, J.L. / Bramlett, K.S. / Briggs, S.L. / Chirgadze, N.Y. / Wang, Y. / Burris, T.P. / Spatola, A.F.
History
DepositionMay 16, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 28, 2003Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Oct 27, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _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

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Assembly

Deposited unit
A: estrogen receptor
B: estrogen receptor
E: peptide inhibitor
F: peptide inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,3636
Polymers57,8184
Non-polymers5452
Water181
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6260 Å2
ΔGint-34 kcal/mol
Surface area20510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.809, 102.432, 195.326
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein estrogen receptor / / ER / Estradiol receptor / ER-alpha


Mass: 27817.594 Da / Num. of mol.: 2 / Fragment: ligand-binding domain / Mutation: C381S, C417S, C530S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P03372
#2: Protein/peptide peptide inhibitor


Mass: 1091.434 Da / Num. of mol.: 2 / Source method: obtained synthetically
Details: The sequence of the peptide is LYS-DCY-ILE-LEU-CYS-ARG-LEU-LEU-GLN.
#3: Chemical ChemComp-EST / ESTRADIOL / Estradiol


Mass: 272.382 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H24O2 / Comment: hormone*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1 / 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: 2.33 Å3/Da / Density % sol: 47.14 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 6.8
Details: MES, LiCl, PEG 6000, pH 6.8, VAPOR DIFFUSION, HANGING DROP, temperature 294K
Crystal grow
*PLUS
Temperature: 294 K / pH: 7 / Method: vapor diffusion
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetailsChemical formula
15 mg/mlprotein1drop
220 mMHEPES1droppH7.0
3100 mM1dropNaCl
40.1 MMES1reservoirpH6.8
51 M1reservoirLiCl
67-15 %PEG60001reservoir

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Sep 21, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→9.99 Å / Num. obs: 14252 / % possible obs: 95.4 % / Biso Wilson estimate: 59.7 Å2
Reflection shellResolution: 2.7→2.87 Å / % possible all: 82.6
Reflection
*PLUS
% possible obs: 95 % / Rmerge(I) obs: 0.114

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Processing

Software
NameVersionClassification
CNX2000.1refinement
HKL-2000data reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→9.99 Å / Rfactor Rfree error: 0.009 / Data cutoff high absF: 1511580.38 / Data cutoff high rms absF: 1511580.38 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.254 719 5 %RANDOM
Rwork0.219 ---
obs-14252 95.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 49.9408 Å2 / ksol: 0.435549 e/Å3
Displacement parametersBiso mean: 47.3 Å2
Baniso -1Baniso -2Baniso -3
1-4.05 Å20 Å20 Å2
2--9.35 Å20 Å2
3----13.4 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.41 Å0.34 Å
Luzzati d res low-5 Å
Luzzati sigma a0.58 Å0.38 Å
Refinement stepCycle: LAST / Resolution: 2.7→9.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3938 0 40 1 3979
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d19.2
X-RAY DIFFRACTIONc_improper_angle_d0.82
X-RAY DIFFRACTIONc_mcbond_it1.291.5
X-RAY DIFFRACTIONc_mcangle_it2.212
X-RAY DIFFRACTIONc_scbond_it2.032
X-RAY DIFFRACTIONc_scangle_it3.22.5
Refine LS restraints NCSNCS model details: CONSTR
LS refinement shellResolution: 2.7→2.87 Å / Rfactor Rfree error: 0.036 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.389 114 5.5 %
Rwork0.309 1949 -
obs--82.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAME2.TOP
X-RAY DIFFRACTION3E2.PARAMCYD.TOP
X-RAY DIFFRACTION4CYD.PARAMWATER.TOP
X-RAY DIFFRACTION5PROTEIN_BREAK.TOP
Refinement
*PLUS
Lowest resolution: 20 Å / Rfactor Rfree: 0.25
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg19.2
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.82

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