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- PDB-5kct: Crystal Structure of the ER-alpha Ligand-binding Domain (Y537S) i... -

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Basic information

Entry
Database: PDB / ID: 5kct
TitleCrystal Structure of the ER-alpha Ligand-binding Domain (Y537S) in Complex with an N-ethyl, 4-chlorobenzyl OBHS-N derivative
Components
  • Estrogen receptor
  • NCOA2
KeywordsTRANSCRIPTION / Nuclear receptor / transcription factor / ligand binding / protein-ligand 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 / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / 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 ...regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / regulation of branching involved in prostate gland morphogenesis / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / 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 / epithelial cell development / prostate epithelial cord elongation / locomotor rhythm / mammary gland branching involved in pregnancy / negative regulation of smooth muscle cell apoptotic process / uterus development / vagina development / aryl hydrocarbon receptor binding / TFIIB-class transcription factor binding / androgen metabolic process / regulation of lipid metabolic process / steroid hormone receptor signaling pathway / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / mammary gland alveolus development / cellular response to estrogen stimulus / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / estrogen response element binding / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear receptor-mediated steroid hormone signaling pathway / negative regulation of canonical NF-kappaB signal transduction / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / Recycling of bile acids and salts / cellular response to hormone stimulus / 14-3-3 protein binding / protein localization to chromatin / estrogen receptor signaling pathway / positive regulation of adipose tissue development / RORA activates gene expression / peroxisome proliferator activated receptor signaling pathway / steroid binding / nitric-oxide synthase regulator activity / Regulation of lipid metabolism by PPARalpha / TBP-class protein binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / regulation of cellular response to insulin stimulus / ESR-mediated signaling / BMAL1:CLOCK,NPAS2 activates circadian gene expression / transcription corepressor binding / negative regulation of miRNA transcription / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / positive regulation of nitric-oxide synthase activity / cellular response to estradiol stimulus / transcription coregulator binding / response to progesterone / nuclear receptor binding / stem cell differentiation / nuclear estrogen receptor binding / positive regulation of DNA-binding transcription factor activity / circadian regulation of gene expression / 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 / euchromatin / negative regulation of DNA-binding transcription factor activity / PPARA activates gene expression / Cytoprotection by HMOX1 / transcription coactivator binding / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / beta-catenin binding / response to estrogen / RNA polymerase II transcription regulator complex / Constitutive Signaling by Aberrant PI3K in Cancer / nuclear receptor activity / male gonad development / Regulation of RUNX2 expression and activity / sequence-specific double-stranded DNA binding / positive regulation of fibroblast proliferation / positive regulation of nitric oxide biosynthetic process / Ovarian tumor domain proteases / Circadian Clock / PIP3 activates AKT signaling / response to estradiol / HATs acetylate histones / ATPase binding / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / regulation of inflammatory response / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / fibroblast proliferation / DNA-binding transcription activator activity, RNA polymerase II-specific
Similarity search - Function
Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / Estrogen receptor / Oestrogen-type nuclear receptor final C-terminal domain / : / Oestrogen receptor / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor/oestrogen-related receptor / Nuclear receptor coactivator, DUF1518 ...Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / Estrogen receptor / Oestrogen-type nuclear receptor final C-terminal domain / : / Oestrogen receptor / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor/oestrogen-related receptor / 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 / 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-OB6 / Chem-OB7 / Estrogen receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.6 Å
AuthorsNwachukwu, J.C. / Srinivasan, S. / Bruno, N.E. / Dharmarajan, V. / Goswami, D. / Kastrati, I. / Novick, S. / Nowak, J. / Zhou, H.B. / Boonmuen, N. ...Nwachukwu, J.C. / Srinivasan, S. / Bruno, N.E. / Dharmarajan, V. / Goswami, D. / Kastrati, I. / Novick, S. / Nowak, J. / Zhou, H.B. / Boonmuen, N. / Zhao, Y. / Min, J. / Frasor, J. / Katzenellenbogen, B.S. / Griffin, P.R. / Katzenellenbogen, J.A. / Nettles, K.W.
CitationJournal: Nat. Chem. Biol. / Year: 2017
Title: Full antagonism of the estrogen receptor without a prototypical ligand side chain.
Authors: Srinivasan, S. / Nwachukwu, J.C. / Bruno, N.E. / Dharmarajan, V. / Goswami, D. / Kastrati, I. / Novick, S. / Nowak, J. / Cavett, V. / Zhou, H.B. / Boonmuen, N. / Zhao, Y. / Min, J. / Frasor, ...Authors: Srinivasan, S. / Nwachukwu, J.C. / Bruno, N.E. / Dharmarajan, V. / Goswami, D. / Kastrati, I. / Novick, S. / Nowak, J. / Cavett, V. / Zhou, H.B. / Boonmuen, N. / Zhao, Y. / Min, J. / Frasor, J. / Katzenellenbogen, B.S. / Griffin, P.R. / Katzenellenbogen, J.A. / Nettles, K.W.
History
DepositionJun 7, 2016Deposition site: RCSB / Processing site: RCSB
SupersessionNov 16, 2016ID: 5BNU
Revision 1.0Nov 16, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 21, 2016Group: Database references
Revision 1.2Dec 28, 2016Group: Database references
Revision 1.3Feb 26, 2020Group: Derived calculations
Category: pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop
Revision 1.4Mar 6, 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

Downloads & links

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Assembly

Deposited unit
A: Estrogen receptor
B: Estrogen receptor
C: NCOA2
D: NCOA2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,9296
Polymers61,9334
Non-polymers9962
Water6,503361
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5140 Å2
ΔGint-28 kcal/mol
Surface area20210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.872, 81.560, 58.914
Angle α, β, γ (deg.)90.000, 110.180, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Estrogen receptor / ER / ER-alpha / Estradiol receptor / Nuclear receptor subfamily 3 group A member 1


Mass: 29299.535 Da / Num. of mol.: 2 / Fragment: ligand-binding domain / Mutation: Y537S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ESR1, ESR, NR3A1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P03372
#2: Protein/peptide NCOA2


Mass: 1666.943 Da / Num. of mol.: 2 / Fragment: Nuclear receptor-interacting peptide / Source method: obtained synthetically / Details: This sequence occurs naturally in humans / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596*PLUS
#3: Chemical ChemComp-OB7 / (1R,2S,4R)-N-(4-chlorophenyl)-N-ethyl-5,6-bis(4-hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide


Mass: 497.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H24ClNO5S
#4: Chemical ChemComp-OB6 / (1S,2R,4S)-N-(4-chlorophenyl)-N-ethyl-5,6-bis(4-hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide


Mass: 497.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H24ClNO5S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 361 / 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 Å3/Da / Density % sol: 38.61 % / Mosaicity: 0.529 °
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 8.3 / Details: 15% PEG 3350, 0.05M MgCl2, 0.067M NaCl, 0.1M Tris

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 27, 2012
RadiationMonochromator: Side scattering bent cube i-beam single crystal asymmetric cut 4.965 degs
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→50 Å / Num. obs: 62319 / % possible obs: 96.9 % / Redundancy: 6.7 % / Rmerge(I) obs: 0.062 / Χ2: 1.269 / Net I/av σ(I): 39.469 / Net I/σ(I): 8.9 / Num. measured all: 414995
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
1.6-1.636.90.72831680.4598.4
1.63-1.666.90.57631390.47398.9
1.66-1.696.90.48431890.49498.9
1.69-1.726.80.41732000.51299.2
1.72-1.766.70.34231250.49898.8
1.76-1.86.40.28331520.55298.5
1.8-1.856.50.23731420.57197.9
1.85-1.970.22832130.84499.3
1.9-1.955.90.24429131.97492
1.95-2.026.90.13631820.78899
2.02-2.096.30.13631451.4297.9
2.09-2.176.50.09331331.10197.8
2.17-2.275.90.09226901.55683.5
2.27-2.397.10.07831851.43999.1
2.39-2.5470.07231621.61599
2.54-2.746.80.0731991.96198.8
2.74-3.016.80.06431352.26697.8
3.01-3.456.90.06131842.54498.1
3.45-4.346.10.05528122.77787
4.34-5070.04332511.98798.3

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.9_1690refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
PHENIXphasing
RefinementResolution: 1.6→46.536 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 23.02
RfactorNum. reflection% reflection
Rfree0.2124 1929 3.25 %
Rwork0.1837 --
obs0.1846 59373 92.07 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 148.97 Å2 / Biso mean: 36.4823 Å2 / Biso min: 14.96 Å2
Refinement stepCycle: final / Resolution: 1.6→46.536 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3806 0 68 361 4235
Biso mean--29.46 43.45 -
Num. residues----481
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074047
X-RAY DIFFRACTIONf_angle_d1.055504
X-RAY DIFFRACTIONf_chiral_restr0.043645
X-RAY DIFFRACTIONf_plane_restr0.005683
X-RAY DIFFRACTIONf_dihedral_angle_d15.0631522
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.5977-1.63760.26751240.23463643376782
1.6376-1.68190.26841250.22313917404289
1.6819-1.73140.27421370.22044045418291
1.7314-1.78730.22551420.21414026416891
1.7873-1.85120.25521460.21384110425693
1.8512-1.92530.31921280.25933816394486
1.9253-2.01290.25871300.2164151428193
2.0129-2.11910.2361480.20034216436495
2.1191-2.25180.22641370.19583998413590
2.2518-2.42570.23511380.18314228436695
2.4257-2.66980.18971500.18314403455399
2.6698-3.0560.19631420.18254370451298
3.056-3.850.19891410.17394231437294
3.85-46.55580.18761410.15974290443194
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.15571.6851-0.68814.6063-0.56042.97160.1799-0.44970.33780.2337-0.35510.1618-0.19250.16640.22960.1947-0.0134-0.01880.2643-0.06130.1752-9.5577-13.32156.0311
22.55410.5737-0.80191.6123-0.8372.2131-0.0694-0.0187-0.1141-0.0892-0.0099-0.02210.1963-0.02010.02740.1738-0.005-0.01340.1437-0.01980.1403-12.3067-20.7477-3.5689
32.8255-0.096-0.41611.50170.01491.7815-0.03720.1335-0.1451-0.0552-0.05270.11310.1078-0.16150.05980.1874-0.0080.01070.12320.00740.1404-11.1785-20.6581-9.2787
41.4240.6425-0.00611.4171-0.22653.849-0.13450.1337-0.0829-0.11510.0638-0.08620.03030.0810.03990.18330.00940.02890.1996-0.00790.1674-1.8991-19.981-34.2233
53.37470.0352-0.06612.3168-0.25864.3342-0.05120.05130.03190.0151-0.00060.0356-0.1315-0.07540.03210.19710.01610.02920.22620.0110.1325-1.0937-17.3529-22.7499
60.9078-0.7538-0.01911.04590.69954.1546-0.06490.0177-0.0666-0.1296-0.10780.0871-0.0048-0.27330.15960.19830.00330.01710.17140.03680.1905-4.009-17.7386-21.9375
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 303:333)A303 - 333
2X-RAY DIFFRACTION2(chain A and resid 334:486)A334 - 486
3X-RAY DIFFRACTION3(chain A and resid 487:548)A487 - 548
4X-RAY DIFFRACTION4(chain B and resid 306:410)B306 - 410
5X-RAY DIFFRACTION5(chain B and resid 411:486)B411 - 486
6X-RAY DIFFRACTION6(chain B and resid 487:548)B487 - 548

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