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

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Basic information

Entry
Database: PDB / ID: 5kce
TitleCrystal Structure of the ER-alpha Ligand-binding Domain (Y537S) in Complex with an N-methyl, 2-chlorobenzyl OBHS-N derivative
Components
  • Estrogen receptor
  • Nuclear receptor coactivator 2
KeywordsTRANSCRIPTION / Nuclear receptor / transcription factor / ligand binding / protein-ligand complex / SIGNALING PROTEIN
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-OB3 / Estrogen receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.847 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 6, 2016Deposition site: RCSB / Processing site: RCSB
SupersessionNov 16, 2016ID: 4ZWH
Revision 1.0Nov 16, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 28, 2016Group: Database references
Revision 1.2Mar 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: Nuclear receptor coactivator 2
D: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,2117
Polymers61,7594
Non-polymers1,4523
Water2,954164
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5240 Å2
ΔGint-30 kcal/mol
Surface area19620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.577, 75.326, 57.996
Angle α, β, γ (deg.)90.000, 110.820, 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, UNP residues 125-381 / 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 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.: 2
Fragment: Nuclear receptor-interacting peptide, 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-OB3 / (1S,2R,4S)-N-(2-chlorophenyl)-5,6-bis(4-hydroxyphenyl)-N-methyl-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide


Mass: 483.964 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C25H22ClNO5S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 164 / 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: 1.74 Å3/Da / Density % sol: 29.23 % / Mosaicity: 1.155 °
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 31, 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: 1.85→41.159 Å / Num. obs: 35083 / % possible obs: 96.7 % / Redundancy: 6.5 % / Biso Wilson estimate: 28.6 Å2 / Rmerge(I) obs: 0.104 / Χ2: 1.161 / Net I/av σ(I): 22.569 / Net I/σ(I): 5.8 / Num. measured all: 227235
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
1.85-1.8860.8117580.46696.6
1.88-1.926.20.79517460.53798.4
1.92-1.956.50.66317820.52498.1
1.95-1.996.50.58317720.50998.3
1.99-2.046.60.50117840.55199
2.04-2.086.50.417700.62498.8
2.08-2.146.40.3317840.61998.1
2.14-2.1960.26717190.70994.5
2.19-2.266.80.26417560.87998.3
2.26-2.336.90.2118070.81398.7
2.33-2.416.90.18817790.82198.2
2.41-2.516.90.15517970.96199.1
2.51-2.636.80.14217881.06498.8
2.63-2.766.50.1217811.20498.6
2.76-2.946.50.10917231.4395.4
2.94-3.166.90.09917691.58497.7
3.16-3.486.50.09117541.95596.1
3.48-3.995.80.08216262.45289
3.99-5.025.80.07516233.01388.8
5.02-506.40.06417653.10593.9

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Processing

Software
NameVersionClassification
PHENIX1.9_1690refinement
HKL-2000data scaling
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.847→41.159 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 0 / Phase error: 27.16 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2496 1871 5.66 %
Rwork0.192 31200 -
obs0.1952 33071 91.01 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 122.75 Å2 / Biso mean: 39.4108 Å2 / Biso min: 18.52 Å2
Refinement stepCycle: final / Resolution: 1.847→41.159 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3747 0 99 164 4010
Biso mean--35.85 41.67 -
Num. residues----480
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0063973
X-RAY DIFFRACTIONf_angle_d0.9675397
X-RAY DIFFRACTIONf_chiral_restr0.036636
X-RAY DIFFRACTIONf_plane_restr0.004660
X-RAY DIFFRACTIONf_dihedral_angle_d15.0341471
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.847-1.89690.37171220.26372025214777
1.8969-1.95270.3091380.24982200233884
1.9527-2.01570.30211330.23252324245788
2.0157-2.08780.24841370.21232371250890
2.0878-2.17140.29731470.19632327247489
2.1714-2.27020.25441390.19392412255192
2.2702-2.38990.25951520.18262515266796
2.3899-2.53960.26341480.1852545269397
2.5396-2.73560.24471560.18442559271597
2.7356-3.01080.24961510.18342518266995
3.0108-3.44630.21141550.18592550270596
3.4463-4.34120.24071410.17782327246888
4.3412-41.1690.24251520.19482527267994
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)
13.93491.67520.62973.44780.56352.7270.1805-0.00560.38230.3069-0.1310.0808-0.2290.0249-0.09780.24170.02650.00350.2106-0.00370.20376.7756-7.022831.7344
26.90053.56130.11857.24830.0324.126-0.0275-0.135-0.15590.48140.05190.1783-0.0817-0.3866-0.02930.25380.04320.00760.29350.0180.1934-5.1392-13.474827.4394
32.1967-0.9607-0.00552.7332-0.16192.43950.05670.076-0.12-0.1122-0.0950.14660.26580.06640.04030.1690.01010.01510.2034-0.01350.17252.8512-18.977121.6954
43.74530.34690.76931.35360.36812.0565-0.06750.0040.1329-0.03260.039-0.1112-0.13630.25860.02380.22370.00090.01570.20160.00420.187711.6832-11.472918.4766
56.0505-0.2888-1.17054.8949-0.57485.8505-0.3272-0.01220.1644-0.3260.22210.46240.0991-0.3022-0.02420.35080.0105-0.09940.4033-0.04660.3958-12.5608-12.654416.7106
64.7124-1.0142.46621.6784-0.67764.85340.03830.5118-0.3083-0.1110.01630.0003-0.16930.7058-0.03420.2366-0.06420.08790.25840.01120.312518.953-12.8656-9.4867
72.5450.58991.01832.1068-0.73054.6076-0.02460.0376-0.163-0.1230.0676-0.00190.23790.2139-0.02310.2298-0.01320.03170.2457-0.00970.192612.0268-19.3797-6.1094
82.0854-2.2423-0.33312.65620.24556.62830.03060.2137-0.05180.0373-0.08290.2517-0.5182-0.5460.00250.5065-0.01820.01090.2750.06270.41313.6867-1.8427-9.7154
92.73972.15432.75583.18810.23146.9453-0.1037-0.48221.3610.1667-0.1680.2305-0.8007-0.40340.27580.49720.0579-0.02970.28480.0070.36057.9183-1.11080.7495
102.3491-0.26460.16622.5528-0.43492.9570.0219-0.0754-0.03060.0989-0.065-0.116-0.08330.32730.05970.2638-0.00340.01830.3331-0.0030.208517.8456-14.90247.4991
115.92571.5831-2.8135.2821.58672.49160.24270.4955-0.4549-0.15880.01370.53360.3685-0.3683-0.10410.4388-0.1042-0.06380.3227-0.01470.42520.5443-24.0791-6.9899
121.7798-0.26751.63843.06910.69472.3632-0.6130.1691-0.5614-0.3848-0.4683-0.09530.87080.2210.72620.58170.08750.10580.3594-0.0740.634312.4579-32.0593-9.5558
133.9995-0.5688-2.01723.1657-1.30672.382-0.5290.2399-0.0126-0.3317-0.45790.96230.3239-0.28960.80190.5025-0.05380.10630.5145-0.09480.6664-10.0926-0.19924.4694
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 303 through 341 )A303 - 341
2X-RAY DIFFRACTION2chain 'A' and (resid 342 through 363 )A342 - 363
3X-RAY DIFFRACTION3chain 'A' and (resid 364 through 437 )A364 - 437
4X-RAY DIFFRACTION4chain 'A' and (resid 438 through 531 )A438 - 531
5X-RAY DIFFRACTION5chain 'A' and (resid 532 through 549 )A532 - 549
6X-RAY DIFFRACTION6chain 'B' and (resid 305 through 338 )B305 - 338
7X-RAY DIFFRACTION7chain 'B' and (resid 339 through 394 )B339 - 394
8X-RAY DIFFRACTION8chain 'B' and (resid 395 through 421 )B395 - 421
9X-RAY DIFFRACTION9chain 'B' and (resid 422 through 438 )B422 - 438
10X-RAY DIFFRACTION10chain 'B' and (resid 439 through 527 )B439 - 527
11X-RAY DIFFRACTION11chain 'B' and (resid 528 through 548 )B528 - 548
12X-RAY DIFFRACTION12chain 'C' and (resid 687 through 696 )C687 - 696
13X-RAY DIFFRACTION13chain 'D' and (resid 688 through 695 )D688 - 695

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