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- PDB-6oqx: Human Liver Receptor Homolog-1 bound to the agonist 5N and a frag... -

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Basic information

Entry
Database: PDB / ID: 6oqx
TitleHuman Liver Receptor Homolog-1 bound to the agonist 5N and a fragment of the Tif2 coregulator
Components
  • Nuclear receptor coactivator 2
  • Nuclear receptor subfamily 5 group A member 2
KeywordsTRANSCRIPTION / Nuclear Hormone Receptor / agonist
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 / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / positive regulation of viral genome replication / Recycling of bile acids and salts / cellular response to hormone stimulus / positive regulation of adipose tissue development / RORA activates gene expression / peroxisome proliferator activated receptor signaling pathway / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / regulation of cellular response to insulin stimulus / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / cholesterol homeostasis / nuclear receptor coactivator activity / cellular response to leukemia inhibitory factor / transcription coregulator binding / response to progesterone / nuclear receptor binding / 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 / PPARA activates gene expression / Cytoprotection by HMOX1 / phospholipid binding / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / nuclear receptor activity / sequence-specific double-stranded DNA binding / Circadian Clock / 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 / nuclear body / protein dimerization activity / transcription cis-regulatory region binding / DNA-binding transcription factor activity, RNA polymerase II-specific / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein domain specific binding / chromatin binding / regulation of DNA-templated transcription / chromatin / 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 / 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-N1V / 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: 2.004 Å
AuthorsMays, S.G. / Ortlund, E.A.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01DK095750 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01DK114213 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)F31DK111171 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32GM008602 United States
CitationJournal: J.Med.Chem. / Year: 2019
Title: Development of the First Low Nanomolar Liver Receptor Homolog-1 Agonist through Structure-guided Design.
Authors: Mays, S.G. / Flynn, A.R. / Cornelison, J.L. / Okafor, C.D. / Wang, H. / Wang, G. / Huang, X. / Donaldson, H.N. / Millings, E.J. / Polavarapu, R. / Moore, D.D. / Calvert, J.W. / Jui, N.T. / Ortlund, E.A.
History
DepositionApr 29, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Jan 8, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.3Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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: Nuclear receptor subfamily 5 group A member 2
C: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,6063
Polymers30,1412
Non-polymers4661
Water1,27971
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1150 Å2
ΔGint-7 kcal/mol
Surface area12320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.547, 46.547, 220.998
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-768-

HOH

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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: 28330.693 Da / Num. of mol.: 1 / Fragment: UNP Residues 299-541
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR5A2, B1F, CPF, FTF / Production host: Escherichia coli (E. coli) / 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: 1810.035 Da / Num. of mol.: 1 / Fragment: UNP Residues 740-754 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596
#3: Chemical ChemComp-N1V / (8beta,11alpha,12alpha)-8-(1-phenylethenyl)-1,6:7,14-dicycloprosta-1,3,5,7(14)-tetraen-11-yl sulfamate


Mass: 465.647 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H35NO3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 71 / 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: 1.99 Å3/Da / Density % sol: 38.06 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: Sodium acetate (pH 4.6), PEG4000, glycerol

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Data collection

DiffractionMean temperature: 273 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Oct 15, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 17346 / % possible obs: 99.91 % / Redundancy: 11.2 % / Net I/σ(I): 21.3
Reflection shellResolution: 2→2.07 Å / Num. unique obs: 1689

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5L11

5l11


Resolution: 2.004→32.052 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.25
RfactorNum. reflection% reflection
Rfree0.2451 867 5 %
Rwork0.2056 --
obs0.2076 17346 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.004→32.052 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2036 0 33 71 2140
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022138
X-RAY DIFFRACTIONf_angle_d0.5042895
X-RAY DIFFRACTIONf_dihedral_angle_d12.081301
X-RAY DIFFRACTIONf_chiral_restr0.034325
X-RAY DIFFRACTIONf_plane_restr0.002368
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0038-2.12930.32891410.26982670X-RAY DIFFRACTION100
2.1293-2.29370.28741390.23332651X-RAY DIFFRACTION100
2.2937-2.52440.25451420.22422708X-RAY DIFFRACTION100
2.5244-2.88950.23971450.2052734X-RAY DIFFRACTION100
2.8895-3.63970.23571440.20682761X-RAY DIFFRACTION100
3.6397-32.05570.23551560.19152955X-RAY DIFFRACTION100
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)
10.482-0.3053-0.06380.255-0.10890.35380.3434-0.49580.07040.76310.1430.59440.27120.20250.00140.4342-0.06840.01270.3974-0.04120.44160.1029-26.43217.624
20.6007-0.39110.12960.39090.0970.7987-0.34070.05920.01470.49080.317-0.0962-0.46280.15630.00030.5914-0.0034-0.03160.4381-0.03960.397213.92420.682727.8625
32.97930.91050.96351.19480.37881.88310.15970.1053-0.05440.2456-0.0866-0.0099-0.02720.20010.00820.28050.04580.00880.2441-0.01080.193913.6214-14.976615.9334
40.7656-0.13460.02730.2955-0.24960.9956-0.1086-0.25570.237-0.23390.04320.2144-0.0561-0.2272-0.02510.5170.0298-0.06680.3256-0.02910.50513.44983.713614.4959
50.4-0.39460.00920.62550.18680.1566-0.23140.46190.6881-0.33010.18440.4145-0.3091-0.2407-0.00060.39480.0417-0.04470.4040.060.46784.2671-2.87744.0211
61.14181.20170.80013.06610.10343.14280.14390.5358-0.0468-0.0597-0.11810.33860.04030.0632-0.00130.2870.0964-0.0360.3034-0.0480.30594.0256-24.61226.5562
70.31580.2092-0.00970.4495-0.35010.34040.29810.00220.0631-0.0363-0.2421-0.00990.09750.105800.43030.0543-0.02490.44290.01890.310113.1806-9.49073.4713
81.2285-0.3936-0.60720.87920.03040.33620.3402-0.41580.50430.5511-0.5954-0.73430.2469-0.36560.02040.735-0.2876-0.13771.05490.32380.629825.81250.337416.659
90.02880.03860.03310.05030.0430.03830.19920.2608-0.0025-0.01150.2218-0.7625-0.25230.4076-0.00020.39650.05820.03210.55080.13680.470624.7631-9.730814.4656
100.26960.08170.07870.09280.10310.11290.2494-0.0079-0.02510.6613-0.2937-0.52380.53190.24850.00010.39-0.0154-0.07330.3955-0.0170.34924.2208-19.684623.5509
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 300 through 314 )
2X-RAY DIFFRACTION2chain 'A' and (resid 315 through 340 )
3X-RAY DIFFRACTION3chain 'A' and (resid 341 through 397 )
4X-RAY DIFFRACTION4chain 'A' and (resid 398 through 421 )
5X-RAY DIFFRACTION5chain 'A' and (resid 422 through 440 )
6X-RAY DIFFRACTION6chain 'A' and (resid 441 through 494 )
7X-RAY DIFFRACTION7chain 'A' and (resid 495 through 522 )
8X-RAY DIFFRACTION8chain 'A' and (resid 523 through 530 )
9X-RAY DIFFRACTION9chain 'A' and (resid 531 through 538 )
10X-RAY DIFFRACTION10chain 'C' and (resid 742 through 752 )

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