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

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Entry
Database: PDB / ID: 5tmm
TitleCrystal Structure of the ER-alpha Ligand-binding Domain (Y537S) in Complex with the OBHS-ASC analog, (E)-6-(4-((1R,4S,6R)-6-((4-bromophenoxy)sulfonyl)-3-(4-hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-2-en-2-yl)phenyl)hex-5-enoic acid
Components
  • Estrogen receptor
  • Nuclear receptor coactivator 2
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 / prostate epithelial cord elongation / epithelial cell development / locomotor rhythm / negative regulation of smooth muscle cell apoptotic process / mammary gland branching involved in pregnancy / uterus development / vagina development / aryl hydrocarbon receptor binding / TFIIB-class transcription factor binding / androgen metabolic process / regulation of lipid metabolic process / steroid hormone mediated signaling pathway / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / mammary gland alveolus development / intracellular estrogen receptor signaling pathway / cellular response to estrogen stimulus / Endogenous sterols / estrogen response element binding / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Nuclear signaling by ERBB4 / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / positive regulation of phospholipase C activity / intracellular steroid hormone receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / RNA polymerase II preinitiation complex assembly / Recycling of bile acids and salts / regulation of cellular response to insulin stimulus / cellular response to hormone stimulus / protein localization to chromatin / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / TBP-class protein binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / Regulation of lipid metabolism by PPARalpha / steroid binding / nitric-oxide synthase regulator activity / ESR-mediated signaling / BMAL1:CLOCK,NPAS2 activates circadian gene expression / 14-3-3 protein binding / transcription corepressor binding / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / Activation of gene expression by SREBF (SREBP) / negative regulation of miRNA transcription / response to progesterone / positive regulation of nitric-oxide synthase activity / cellular response to estradiol stimulus / nuclear estrogen receptor binding / transcription coregulator binding / stem cell differentiation / nuclear receptor binding / circadian regulation of gene expression / euchromatin / 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 / negative regulation of DNA-binding transcription factor activity / transcription coactivator binding / PPARA activates gene expression / Cytoprotection by HMOX1 / beta-catenin binding / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / response to estrogen / RNA polymerase II transcription regulator complex / male gonad development / Regulation of RUNX2 expression and activity / Constitutive Signaling by Aberrant PI3K in Cancer / nuclear receptor activity / positive regulation of nitric oxide biosynthetic process / positive regulation of DNA-binding transcription factor activity / positive regulation of fibroblast proliferation / Ovarian tumor domain proteases / Circadian Clock / sequence-specific double-stranded DNA binding / response to estradiol / PIP3 activates AKT signaling / phospholipase C-activating G protein-coupled receptor signaling pathway / HATs acetylate histones / ATPase binding / positive regulation of cytosolic calcium ion concentration / fibroblast proliferation / regulation of inflammatory response / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
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 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-7M4 / Estrogen receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsNwachukwu, J.C. / Srinivasan, S. / Bruno, N.E. / Nowak, J. / Kojetin, D.J. / Elemento, O. / Katzenellenbogen, J.A. / Nettles, K.W.
CitationJournal: Cell Chem Biol / Year: 2017
Title: Systems Structural Biology Analysis of Ligand Effects on ER alpha Predicts Cellular Response to Environmental Estrogens and Anti-hormone Therapies.
Authors: Nwachukwu, J.C. / Srinivasan, S. / Bruno, N.E. / Nowak, J. / Wright, N.J. / Minutolo, F. / Rangarajan, E.S. / Izard, T. / Yao, X.Q. / Grant, B.J. / Kojetin, D.J. / Elemento, O. / ...Authors: Nwachukwu, J.C. / Srinivasan, S. / Bruno, N.E. / Nowak, J. / Wright, N.J. / Minutolo, F. / Rangarajan, E.S. / Izard, T. / Yao, X.Q. / Grant, B.J. / Kojetin, D.J. / Elemento, O. / Katzenellenbogen, J.A. / Nettles, K.W.
History
DepositionOct 13, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 18, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 1, 2017Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software
Revision 1.3Mar 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)62,9826
Polymers61,7594
Non-polymers1,2232
Water3,297183
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5140 Å2
ΔGint-31 kcal/mol
Surface area18430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.090, 82.520, 58.740
Angle α, β, γ (deg.)90.00, 111.14, 90.00
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-7M4 / 6-{4-[(1S,4S,6S)-6-[(4-bromophenoxy)sulfonyl]-3-(4-hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-2-en-2-yl]phenyl}hex-5-enoic acid


Mass: 611.500 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H27BrO7S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 183 / 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: 2.02 Å3/Da / Density % sol: 39 % / Mosaicity: 0.396 °
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: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 25, 2014
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: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.2→45.64 Å / Num. obs: 24297 / % possible obs: 97.5 % / Redundancy: 6.9 % / Biso Wilson estimate: 23.44 Å2 / Rmerge(I) obs: 0.091 / Net I/σ(I): 4.3
Reflection shellResolution: 2.2→2.24 Å / Redundancy: 6.2 % / Rmerge(I) obs: 0.521 / % possible all: 93

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
HKL-2000data scaling
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
PHENIXphasing
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→45.64 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 0 / Phase error: 26.07
RfactorNum. reflection% reflection
Rfree0.251 1756 8.23 %
Rwork0.205 --
obs0.209 21330 85.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 42.14 Å2
Refinement stepCycle: LAST / Resolution: 2.2→45.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3559 0 57 183 3799
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0023717
X-RAY DIFFRACTIONf_angle_d0.3955041
X-RAY DIFFRACTIONf_dihedral_angle_d11.9641319
X-RAY DIFFRACTIONf_chiral_restr0.03605
X-RAY DIFFRACTIONf_plane_restr0.002618
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2029-2.26250.2561500.2716560X-RAY DIFFRACTION32
2.2625-2.3290.2865830.26681052X-RAY DIFFRACTION60
2.329-2.40420.32481370.29141419X-RAY DIFFRACTION81
2.4042-2.49010.28961380.24391523X-RAY DIFFRACTION87
2.4901-2.58980.30061320.23851575X-RAY DIFFRACTION91
2.5898-2.70770.28151480.2271608X-RAY DIFFRACTION92
2.7077-2.85040.30151470.23031545X-RAY DIFFRACTION89
2.8504-3.02890.27071420.21651677X-RAY DIFFRACTION96
3.0289-3.26280.2661610.21861722X-RAY DIFFRACTION97
3.2628-3.5910.24591500.20251711X-RAY DIFFRACTION98
3.591-4.11030.19951490.16581698X-RAY DIFFRACTION96
4.1103-5.17740.22961520.16281735X-RAY DIFFRACTION98
5.1774-45.6530.2171670.19091749X-RAY DIFFRACTION97
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)
12.71842.23-1.03593.43810.23275.1125-0.40550.1024-0.7906-0.2960.0857-0.45120.35990.72760.20150.21310.08230.18330.39570.11140.302513.26354.046221.2652
25.00191.65430.19263.4579-0.46026.5702-0.7280.3621-0.0688-0.29790.3108-0.06320.8531-0.79410.20550.3986-0.09280.12710.356-0.06210.20981.6272-0.253217.2452
32.90651.1635-1.53963.68160.35734.9621-0.35370.2187-0.2117-0.45670.0875-0.15550.5967-0.10210.14820.3011-0.00120.06410.15340.01550.16324.55152.637524.7797
43.88150.6291-0.65264.2999-0.88165.8623-0.03950.30920.25020.05530.00210.2979-0.481-0.35980.09250.18820.08060.03460.20870.06960.16651.775511.530128.6158
50.8099-1.66461.49343.4533-3.29285.4927-0.3578-0.3461-0.57950.54950.14930.03051.23490.0590.22761.17170.18270.30890.42830.13960.51875.1465-8.746738.9382
64.18090.6538-1.03842.811-0.43655.0541-0.0693-0.1921-0.10320.0829-0.2089-0.16940.13170.68530.10370.1080.022-0.01370.27080.06850.15418.1096.280136.7234
74.6012.37530.12191.8464-0.51063.7946-0.86970.9299-0.6705-0.94840.07070.66441.2258-1.44270.26390.8423-0.39170.06290.7647-0.12440.6893-6.5861-8.373422.5505
85.02190.9069-1.12032.6292-0.67274.91130.1744-0.2670.24970.4177-0.18180.313-0.1334-0.05220.02540.209-0.02650.05040.1783-0.04960.1693-8.16486.784555.144
92.7047-0.5747-0.76684.43510.23034.578-0.3326-0.1517-1.00610.0272-0.22380.32671.6049-0.1176-0.1150.8218-0.00780.18860.23960.05190.435-7.6537-12.585553.9502
104.76391.1526-0.83025.1333-0.16434.8035-0.0969-0.0564-0.28080.227-0.1804-0.0440.47120.48910.21240.22120.01090.01680.21420.00330.1170.9980.152349.2284
113.93820.9171-0.75252.9979-0.2974.7421-0.0018-0.36050.14140.1595-0.3026-0.15680.11040.5330.14770.2219-0.0004-0.0320.27870.04040.13324.90595.815846.7179
125.48171.3693-0.92864.8511-0.70915.32540.25990.68580.4120.197-0.13120.91720.5068-1.67670.07680.2773-0.0587-0.04360.6743-0.0620.453-20.2475.847945.4462
130.46881.51831.40255.713.99964.5225-0.15860.4236-0.8161-0.11240.0543-0.07030.66130.0035-0.53291.2622-0.10590.38250.2714-0.31180.63485.4958-14.01619.9603
143.5878-0.24212.26361.35810.30775.7298-0.1201-0.4202-0.172-0.2546-0.11090.25-0.6746-1.61420.36430.43970.15190.28360.5667-0.08071.0135-19.152416.522853.7916
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN 'A' AND (RESID 306 THROUGH 338 )
2X-RAY DIFFRACTION2CHAIN 'A' AND (RESID 339 THROUGH 363 )
3X-RAY DIFFRACTION3CHAIN 'A' AND (RESID 364 THROUGH 410 )
4X-RAY DIFFRACTION4CHAIN 'A' AND (RESID 411 THROUGH 455 )
5X-RAY DIFFRACTION5CHAIN 'A' AND (RESID 456 THROUGH 472 )
6X-RAY DIFFRACTION6CHAIN 'A' AND (RESID 473 THROUGH 529 )
7X-RAY DIFFRACTION7CHAIN 'A' AND (RESID 530 THROUGH 548 )
8X-RAY DIFFRACTION8CHAIN 'B' AND (RESID 305 THROUGH 394 )
9X-RAY DIFFRACTION9CHAIN 'B' AND (RESID 395 THROUGH 421 )
10X-RAY DIFFRACTION10CHAIN 'B' AND (RESID 422 THROUGH 472 )
11X-RAY DIFFRACTION11CHAIN 'B' AND (RESID 473 THROUGH 528 )
12X-RAY DIFFRACTION12CHAIN 'B' AND (RESID 529 THROUGH 548 )
13X-RAY DIFFRACTION13CHAIN 'C' AND (RESID 688 THROUGH 695 )
14X-RAY DIFFRACTION14CHAIN 'D' AND (RESID 688 THROUGH 696 )

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