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- PDB-7tt8: Human LRH-1 LBD bound to agonist 6N-10CA and fragment of Tif2 coa... -

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Basic information

Entry
Database: PDB / ID: 7tt8
TitleHuman LRH-1 LBD bound to agonist 6N-10CA and fragment of Tif2 coactivator
Components
  • Nuclear receptor coactivator 2
  • Nuclear receptor subfamily 5 group A member 2
KeywordsNUCLEAR PROTEIN / LRH-1 / Nuclear Receptor / Ligand / Synthetic Agonist
Function / homology
Function and homology information


positive regulation of glucocorticoid biosynthetic process / zygotic genome activation / positive regulation of tendon cell differentiation / morula formation / Regulation of gene expression in early pancreatic precursor cells / primary ovarian follicle growth / pancreas morphogenesis / inner cell mass cell differentiation / tissue development / acinar cell differentiation ...positive regulation of glucocorticoid biosynthetic process / zygotic genome activation / positive regulation of tendon cell differentiation / morula formation / Regulation of gene expression in early pancreatic precursor cells / primary ovarian follicle growth / pancreas morphogenesis / inner cell mass cell differentiation / tissue development / acinar cell differentiation / Sertoli cell development / positive regulation of stem cell differentiation / positive regulation of T cell anergy / embryonic cleavage / bile acid metabolic process / embryo development ending in birth or egg hatching / exocrine pancreas development / cartilage development / negative regulation of chondrocyte differentiation / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / homeostatic process / locomotor rhythm / calcineurin-mediated signaling / aryl hydrocarbon receptor binding / cellular response to Thyroglobulin triiodothyronine / regulation of lipid metabolic process / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / somatic stem cell population maintenance / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / positive regulation of viral genome replication / cellular response to hormone stimulus / Recycling of bile acids and salts / transcription regulator inhibitor activity / hormone-mediated signaling pathway / : / positive regulation of adipose tissue development / neurogenesis / Regulation of lipid metabolism by PPARalpha / positive regulation of T cell proliferation / peroxisome proliferator activated receptor signaling pathway / regulation of cellular response to insulin stimulus / BMAL1:CLOCK,NPAS2 activates circadian expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / response to progesterone / cholesterol homeostasis / cellular response to leukemia inhibitory factor / nuclear receptor binding / transcription coregulator binding / negative regulation of smoothened signaling pathway / SUMOylation of intracellular receptors / circadian regulation of gene expression / mRNA transcription by RNA polymerase II / Heme signaling / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Cytoprotection by HMOX1 / phospholipid binding / positive regulation of T cell activation / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / negative regulation of inflammatory response / RNA polymerase II transcription regulator complex / nuclear receptor activity / sequence-specific double-stranded DNA binding / : / HATs acetylate histones / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / DNA-binding transcription activator activity, RNA polymerase II-specific / spermatogenesis / transcription regulator complex / Estrogen-dependent gene expression / sequence-specific DNA binding / DNA-binding transcription factor activity, RNA polymerase II-specific / transcription coactivator activity / transcription cis-regulatory region binding / protein dimerization activity / nuclear body / RNA polymerase II cis-regulatory region sequence-specific DNA binding / chromatin remodeling / DNA-binding transcription factor activity / protein domain specific binding / chromatin binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / chromatin / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / DNA binding / zinc ion binding / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
Nuclear hormone receptor family 5 / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / 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 hormone receptor family 5 / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / 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 / Nuclear receptor coactivators bHLH domain / 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 / PAS domain superfamily / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Double treble clef zinc finger, C4 type / 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
Similarity search - Domain/homology
Chem-IUW / Nuclear receptor subfamily 5 group A member 2 / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsCato, M.L. / Ortlund, E.A.
Funding support United States, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)F31DK122745 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01-DK115213 United States
National Science Foundation (NSF, United States)DGE-1444932 United States
American Heart Association20PRE35200311 United States
Department of Health & Human Services (HHS)NIH P51 OD011132 United States
Citation
Journal: J.Med.Chem. / Year: 2022
Title: Differential Modulation of Nuclear Receptor LRH-1 through Targeting Buried and Surface Regions of the Binding Pocket.
Authors: Cato, M.L. / Cornelison, J.L. / Spurlin, R.M. / Courouble, V.V. / Patel, A.B. / Flynn, A.R. / Johnson, A.M. / Okafor, C.D. / Frank, F. / D'Agostino, E.H. / Griffin, P.R. / Jui, N.T. / Ortlund, E.A.
#1: Journal: Acta Crystallogr D Biol Crystallogr / Year: 2010
Title: PHENIX: a comprehensive Python-based system for macromolecular structure solution.
Authors: Adams, P.D. / Afonine, P.V. / Bunkoczi, G. / Chen, V.B. / Davis, I.W. / Echols, N. / Headd, J.J. / Hung, L.W. / Kapral, G.J. / Grosse-Kunstleve, R.W. / McCoy, A.J. / Moriarty, N.W. / ...Authors: Adams, P.D. / Afonine, P.V. / Bunkoczi, G. / Chen, V.B. / Davis, I.W. / Echols, N. / Headd, J.J. / Hung, L.W. / Kapral, G.J. / Grosse-Kunstleve, R.W. / McCoy, A.J. / Moriarty, N.W. / Oeffner, R. / Read, R.J. / Richardson, D.C. / Richardson, J.S. / Terwilliger, T.C. / Zwart, P.H.
#2: Journal: Acta Crystallogr D Biol Crystallogr / Year: 2010
Title: Features and development of Coot.
Authors: Emsley, P. / Lohkamp, B. / Scott, W.G. / Cowtan, K.
History
DepositionJan 31, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 11, 2022Provider: repository / Type: Initial release
Revision 1.1May 18, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2May 25, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Jun 22, 2022Group: Refinement description / Category: refine / software / Item: _refine.pdbx_ls_cross_valid_method / _software.name
Revision 1.4Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Nuclear receptor subfamily 5 group A member 2
C: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,6613
Polymers30,1112
Non-polymers5511
Water1,17165
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint-8 kcal/mol
Surface area11870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)88.302, 88.302, 105.605
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Space group name HallP322"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3
#4: x-y,-y,-z+1/3
#5: -x,-x+y,-z+2/3
#6: y,x,-z

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Components

#1: Protein Nuclear receptor subfamily 5 group A member 2 / Alpha-1-fetoprotein transcription factor / B1-binding factor / hB1F / CYP7A promoter-binding factor ...Alpha-1-fetoprotein transcription factor / B1-binding factor / hB1F / CYP7A promoter-binding factor / Hepatocytic transcription factor / Liver receptor homolog 1 / LRH-1


Mass: 28401.771 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR5A2, B1F, CPF, FTF / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: O00482
#2: Protein/peptide Nuclear receptor coactivator 2 / NCoA-2 / Class E basic helix-loop-helix protein 75 / bHLHe75 / Transcriptional intermediary factor 2 / hTIF2


Mass: 1708.931 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596
#3: Chemical ChemComp-IUW / 10-[(3aR,6S,6aR)-3-phenyl-3a-(1-phenylethenyl)-6-(sulfamoylamino)-1,3a,4,5,6,6a-hexahydropentalen-2-yl]decanoic acid (non-preferred name)


Mass: 550.752 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H42N2O4S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 65 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 4.19 Å3/Da / Density % sol: 70.66 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / Details: tri-Na citrate (4.6), tert-butanol, glycerol

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 4, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→35.2 Å / Num. obs: 11868 / % possible obs: 97.9 % / Redundancy: 5.4 % / Biso Wilson estimate: 45.17 Å2 / CC1/2: 0.978 / Net I/σ(I): 7.7
Reflection shellResolution: 2.8→2.9 Å / Num. unique obs: 1181 / CC1/2: 0.72

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5L11

5l11


Resolution: 2.8→35.2 Å / SU ML: 0.3541 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 28.4437 / Stereochemistry target values: CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2759 1188 10.02 %
Rwork0.2288 10669 -
obs0.2337 11857 97.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 55.31 Å2
Refinement stepCycle: LAST / Resolution: 2.8→35.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1988 0 39 65 2092
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00262064
X-RAY DIFFRACTIONf_angle_d0.50082789
X-RAY DIFFRACTIONf_chiral_restr0.0338315
X-RAY DIFFRACTIONf_plane_restr0.005352
X-RAY DIFFRACTIONf_dihedral_angle_d2.75781247
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.930.33031480.27861344X-RAY DIFFRACTION98.87
2.93-3.090.30911430.28391300X-RAY DIFFRACTION98.57
3.09-3.280.30131500.26481340X-RAY DIFFRACTION98.61
3.28-3.530.30411460.24011315X-RAY DIFFRACTION98.05
3.53-3.890.27741460.21381317X-RAY DIFFRACTION98.58
3.89-4.450.22521470.19311338X-RAY DIFFRACTION98.08
4.45-5.60.25451480.20061331X-RAY DIFFRACTION97.17
5.6-35.20.28321600.23941384X-RAY DIFFRACTION96.08
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)
14.165426616813.412818564073.039023040953.312824328421.4740200812.99553190649-1.12316975296-0.5361375479591.546717987540.04991433066680.006580903249192.25625578998-1.126831629130.03159864932260.2944225729090.6640354467080.0918845446971-0.1236298613630.284782118773-0.1467487062460.77291767231124.1187062264-6.27036716235-11.8493094603
24.627662260263.611207898860.8737837430435.245633880060.609654061863.83229817775-0.1639652602570.003178352848390.499011767147-0.01873003417650.06268741485190.39806843669-0.329316425995-0.303671622038-0.0181938738850.3159564717480.023705487851-0.07467740176360.1608016611320.003474599112010.32764429514731.1980013129-11.6817376768-8.21504343671
33.681000323611.523082644131.235099712583.662802642611.711817413224.23012169064-0.1791720698570.526229852541-0.171610219402-0.3421616121450.21311286207-0.0820935862079-0.1887430016210.2852634564340.03266530013430.217239696781-0.02699342937-0.0001706415459160.122148063398-0.001025264653740.17088190647533.7011515444-22.2633348853-17.8027042135
43.812168046241.036667402463.579530754763.016532349380.7053615907583.61295142634-0.0107066624836-0.345628110553-0.1280913467280.527290239468-0.0655399194980.03280866047380.434312178013-0.1582161640640.09815932380410.250831893773-0.0687268496713-0.006320974535040.1609029139770.003751181145410.31828143058937.2530241311-17.4529675065-3.02673820149
59.06744062421-5.513998648032.503619105197.27761538635-0.6842461276136.60350470428-0.201886033637-1.34488087316-0.4979406968471.02902963684-0.1430266865891.51795865491-0.470473976536-0.799847512460.4265541426460.546465714106-0.1174243264880.1881828065240.7146648935-0.3727842884960.72878681416317.5081223003-17.57582900912.23879828064
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 300 through 340 )
2X-RAY DIFFRACTION2chain 'A' and (resid 341 through 421 )
3X-RAY DIFFRACTION3chain 'A' and (resid 422 through 492 )
4X-RAY DIFFRACTION4chain 'A' and (resid 493 through 538 )
5X-RAY DIFFRACTION5chain 'C' and (resid 742 through 751 )

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