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- PDB-8f8m: LRH-1 bound to small molecule Tet and fragment of coactivator Tif2 -

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Basic information

Entry
Database: PDB / ID: 8f8m
TitleLRH-1 bound to small molecule Tet and fragment of coactivator Tif2
Components
  • Nuclear receptor coactivator 2
  • Nuclear receptor subfamily 5 group A member 2
KeywordsNUCLEAR PROTEIN / LRH-1 / NR5A2 / Nuclear Receptor / Liver receptor homolog-1
Function / homology
Function and homology information


Regulation of gene expression in early pancreatic precursor cells / pancreas morphogenesis / calcineurin-mediated signaling / acinar cell differentiation / tissue development / bile acid metabolic process / embryo development ending in birth or egg hatching / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / homeostatic process / locomotor rhythm ...Regulation of gene expression in early pancreatic precursor cells / pancreas morphogenesis / calcineurin-mediated signaling / acinar cell differentiation / tissue development / bile acid metabolic process / embryo development ending in birth or egg hatching / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / homeostatic process / locomotor rhythm / aryl hydrocarbon receptor binding / regulation of lipid metabolic process / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / positive regulation of viral genome replication / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / regulation of cellular response to insulin stimulus / Recycling of bile acids and salts / cellular response to hormone stimulus / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / Regulation of lipid metabolism by PPARalpha / cellular response to leukemia inhibitory factor / hormone-mediated signaling pathway / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / response to progesterone / cholesterol homeostasis / transcription coregulator binding / nuclear receptor binding / phospholipid binding / circadian regulation of gene expression / Heme signaling / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / nuclear receptor activity / Circadian Clock / sequence-specific double-stranded DNA binding / regulation of cell population proliferation / HATs acetylate histones / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / transcription regulator complex / sequence-specific DNA binding / transcription coactivator activity / transcription cis-regulatory region binding / nuclear body / protein dimerization activity / DNA-binding transcription factor activity, RNA polymerase II-specific / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein domain specific binding / chromatin binding / chromatin / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / 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 / PAS domain / 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. / Nuclear receptor coactivator, interlocking / 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 / 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
Similarity search - Domain/homology
Chem-XKE / 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: 2.6 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)F31-DK122745 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01-DK115213 United States
American Heart Association20PRE35200311 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32-GM008367-29 United States
National Science Foundation (NSF, United States)DGE-1444932 United States
CitationJournal: To Be Published
Title: Isosteric improvements to liver receptor homolog-1 small molecule modulators
Authors: Cato, M.L. / Abraham, S.M. / Spurlin, R.M. / Flynn, A.R. / Colucci, J.K. / D'Agostino, E.H. / Johnson, A.M. / Jui, N.T. / Ortlund, E.A.
History
DepositionNov 22, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 29, 2023Provider: repository / Type: Initial release

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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
B: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,6073
Polymers30,1112
Non-polymers4971
Water52229
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1130 Å2
ΔGint-7 kcal/mol
Surface area12160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)89.161, 89.161, 105.692
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 / Fragment: Nuclear receptor ligand-binding domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR5A2, B1F, CPF, FTF / Production host: Escherichia coli BL21(DE3) (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-XKE / (1~{R},3~{a}~{R},6~{a}~{R})-4-phenyl-3~{a}-(1-phenylethenyl)-5-[9-(1~{H}-1,2,3,4-tetrazol-5-yl)nonyl]-2,3,6,6~{a}-tetrahydro-1~{H}-pentalen-1-ol


Mass: 496.686 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H40N4O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 29 / 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: 4.03 Å3/Da / Density % sol: 69.46 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / Details: tri-Na citrate, 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: Feb 20, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→44.6 Å / Num. obs: 15066 / % possible obs: 97.7 % / Redundancy: 11.2 % / CC1/2: 0.937 / Net I/σ(I): 12.1
Reflection shellResolution: 2.6→2.69 Å / Mean I/σ(I) obs: 1.38 / Num. unique obs: 1235 / CC1/2: 0.57

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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: 4DOS

4dos


Resolution: 2.6→44.58 Å / Cross valid method: FREE R-VALUE / σ(F): 184.17 / Phase error: 28.8326 / Stereochemistry target values: CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2196 1504 9.98 %
Rwork0.196 13562 -
obs0.2033 15066 97.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 67.91 Å2
Refinement stepCycle: LAST / Resolution: 2.6→44.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2041 0 37 29 2107
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00232118
X-RAY DIFFRACTIONf_angle_d0.47992860
X-RAY DIFFRACTIONf_chiral_restr0.0346321
X-RAY DIFFRACTIONf_plane_restr0.003363
X-RAY DIFFRACTIONf_dihedral_angle_d5.94311282
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.680.29661140.28991015X-RAY DIFFRACTION74.09
2.68-2.780.32861360.27531219X-RAY DIFFRACTION88.78
2.78-2.890.24571350.25821237X-RAY DIFFRACTION90.16
2.89-3.020.32941370.2611239X-RAY DIFFRACTION90.04
3.02-3.180.24291390.24381247X-RAY DIFFRACTION89.97
3.18-3.380.22731350.22171246X-RAY DIFFRACTION90.22
3.38-3.640.21021410.19661257X-RAY DIFFRACTION89.91
3.64-4.010.19121350.18931232X-RAY DIFFRACTION89.6
4.01-4.590.19161440.16991267X-RAY DIFFRACTION89.04
4.59-5.780.19281370.17741273X-RAY DIFFRACTION90.09
5.78-36.270.23891460.18851319X-RAY DIFFRACTION87.87
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)
10.2297297878380.0010508336812-0.4928684408921.833373074430.4613254206251.21828949197-0.246856450732-1.17284870924-0.129338803807-0.3327873097180.1105452233190.618636653317-1.28402778841-2.04540438153-0.02007917258070.483702326680.06097417198950.02602321146870.7145166923580.01100991198780.56895920022426.8727447203-9.6398725865223.9481696758
20.9462580995020.955843826744-0.1858028258450.90447376929-0.1640828822950.3565793452470.290692794438-0.1916633374880.135023161615-0.906402767651-0.4430028680360.4538196950380.0886609176825-1.36605881577-0.003099056772490.804812764363-0.055823657882-0.02604333219440.850116161152-0.1189934948870.8885792725411.4101950429-25.80459336491.348235566
30.817913592357-1.101443605250.209139516181.67649002203-0.5999086667030.540500647029-0.5121089484020.4080062327860.3667837860150.1633046930880.5667353432961.36666203646-0.2839955644350.130805118907-0.0005183606080660.6571595132020.0162357071262-0.04545183786330.690237177442-0.01494920655830.50369579754324.826624715-14.01643509995.97004891289
42.05281722857-0.713077435901-0.5720361930371.84493671672.142801821122.55074936444-0.289432457636-0.08807590004090.0193319898527-0.07868878050970.1069557509450.3382865913590.32871173632-0.5227004453270.001222094581140.542988483269-0.0698089175542-0.03486047038980.518918798622-0.0223972477850.37961223516227.9842562718-21.61061260910.2405200062
50.445928112560.009100304756730.7065955705772.037335246331.781163646334.190950897790.156765618509-0.124473783213-0.06307365659620.609044389871-0.137014262631-0.1355385893680.439524943904-0.04731549489455.81333430156E-50.54566877735-0.06583705869520.005769675203280.460942110152-0.004376028796830.39658193179232.7266803444-25.015424136812.9712648214
63.31671851619-0.598289051221.592390976031.982198586321.212812804942.04524124658-0.662854451537-0.477725581599-0.4023751770170.13748444719-0.118071991799-1.117327533720.07596551721730.453657187534-0.0145965692310.4745488332890.06966644482430.03447548560580.4698562975110.01032049806650.4415633319939.9518014225-13.085116267424.5073262566
71.21508835883-0.305268945347-1.12233304211.87381666180.5207703686131.05336517928-0.03796585776790.256088031124-0.0817676416973-0.145702004527-0.0439695395031-0.214246055363-0.008997824595310.0899955907001-0.001718499842110.459848506951-0.01986504852320.02141551659880.4072268314730.009569671614580.44479545998537.3367976371-25.11721081865.82315768556
81.007083111830.1367980660440.08919513029550.2334510084910.3555582199720.7557551086450.1445495522481.939747106680.850207569923-1.06891836824-0.530864650140.0582646240653-0.585450506983-0.7843372823460.02104720126071.02305245141-0.0202477701318-0.2611058857770.858793266385-0.0562110708360.65472559487125.8641402183-20.03617456-6.9558576072
90.4054972883950.5440190322550.03936203422641.023561615480.155477693790.0804058177682-0.08310959266730.1038698529951.49269752318-0.5482729325080.4039227120530.932078797066-0.4252015644931.508321117010.01829023578730.963630175448-0.217419120069-0.2763911623630.8366612527830.08124572115010.91753112156724.5337373451-5.26106030922-1.93281084695
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 299 through 314 )
2X-RAY DIFFRACTION2chain 'A' and (resid 315 through 340 )
3X-RAY DIFFRACTION3chain 'A' and (resid 341 through 370 )
4X-RAY DIFFRACTION4chain 'A' and (resid 371 through 409 )
5X-RAY DIFFRACTION5chain 'A' and (resid 410 through 466 )
6X-RAY DIFFRACTION6chain 'A' and (resid 467 through 494 )
7X-RAY DIFFRACTION7chain 'A' and (resid 495 through 523 )
8X-RAY DIFFRACTION8chain 'A' and (resid 524 through 538 )
9X-RAY DIFFRACTION9chain 'B' and (resid 742 through 752 )

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