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- PDB-6kke: THRb mutation with a novel agonist -

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Basic information

Entry
Database: PDB / ID: 6kke
TitleTHRb mutation with a novel agonist
Components
  • SRC2-3
  • Thyroid hormone receptor beta
KeywordsTRANSCRIPTION / agonist / thyroid hormone receptor / anemia
Function / homology
Function and homology information


retinal cone cell apoptotic process / negative regulation of female receptivity / female courtship behavior / retinal cone cell development / thyroid hormone mediated signaling pathway / positive regulation of thyroid hormone mediated signaling pathway / cellular response to thyroid hormone stimulus / regulation of heart contraction / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / type I pneumocyte differentiation ...retinal cone cell apoptotic process / negative regulation of female receptivity / female courtship behavior / retinal cone cell development / thyroid hormone mediated signaling pathway / positive regulation of thyroid hormone mediated signaling pathway / cellular response to thyroid hormone stimulus / regulation of heart contraction / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / type I pneumocyte differentiation / thyroid hormone binding / 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 / retinoic acid receptor signaling pathway / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Recycling of bile acids and salts / regulation of cellular response to insulin stimulus / 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 / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / Activation of gene expression by SREBF (SREBP) / response to progesterone / nuclear receptor binding / sensory perception of sound / 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 / transcription coactivator binding / PPARA activates gene expression / Cytoprotection by HMOX1 / chromatin DNA binding / 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 / HATs acetylate histones / Estrogen-dependent gene expression / transcription regulator complex / cell differentiation / transcription coactivator activity / protein dimerization activity / nuclear body / 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 / DNA-templated transcription / chromatin binding / chromatin / regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / enzyme binding / positive regulation of transcription by RNA polymerase II / protein-containing complex / DNA binding / zinc ion binding / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
Thyroid hormone receptor / 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 ...Thyroid hormone receptor / 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 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-8HO / Thyroid hormone receptor beta / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.577 Å
AuthorsYao, B.Q. / Li, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Science Foundation (China)U1405220 China
Citation
Journal: Iscience / Year: 2019
Title: Revealing a Mutant-Induced Receptor Allosteric Mechanism for the Thyroid Hormone Resistance.
Authors: Yao, B. / Wei, Y. / Zhang, S. / Tian, S. / Xu, S. / Wang, R. / Zheng, W. / Li, Y.
#1: Journal: Adv. Drug Deliv. Rev. / Year: 2010
Title: Structural and functional insights into nuclear receptor signaling
Authors: Jin, L. / Li, Y.
History
DepositionJul 25, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 23, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 22, 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: Thyroid hormone receptor beta
C: SRC2-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,8203
Polymers29,4672
Non-polymers3521
Water73941
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1040 Å2
ΔGint-7 kcal/mol
Surface area12120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)106.732, 106.732, 57.079
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein Thyroid hormone receptor beta / / Nuclear receptor subfamily 1 group A member 2 / c-erbA-2 / c-erbA-beta


Mass: 28117.693 Da / Num. of mol.: 1 / Mutation: H435L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: THRB, ERBA2, NR1A2, THR1 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P10828
#2: Protein/peptide SRC2-3


Mass: 1349.576 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q15596*PLUS
#3: Chemical ChemComp-8HO / 2-[(1-methyl-4-oxidanyl-7-phenoxy-isoquinolin-3-yl)carbonylamino]ethanoic acid / Roxadustat


Mass: 352.341 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H16N2O5 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, inhibitor*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 41 / 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: 2.82 Å3/Da / Density % sol: 56.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.2 M Ammonium citrate tribasic pH 7.0, 20% w/v Polyethylene glycol 3,350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: May 31, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.57→30 Å / Num. obs: 10873 / % possible obs: 99.9 % / Redundancy: 11.3 % / Rmerge(I) obs: 0.272 / Rpim(I) all: 0.084 / Rrim(I) all: 0.285 / Χ2: 0.963 / Net I/σ(I): 7.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.57-2.619.34.0325280.4421.3824.2680.93199.6
2.61-2.669.85.0165180.4561.6595.2880.968100
2.66-2.7110.13.6375430.5561.1833.8290.923100
2.71-2.77113.1765160.6860.9933.330.914100
2.77-2.8311.22.9065280.7060.8973.0440.931100
2.83-2.8911.92.6575420.8550.7952.7760.96100
2.89-2.9712.52.2735330.8770.6632.3690.95100
2.97-3.0512.51.965300.8930.5712.0430.943100
3.05-3.1412.71.515420.9250.4391.5740.941100
3.14-3.2412.51.195270.930.3481.2410.935100
3.24-3.3512.10.7895530.9680.2350.8240.97100
3.35-3.4911.70.5675200.9730.170.5921.047100
3.49-3.6510.20.3915460.9660.1290.4131.07799.5
3.65-3.8412.30.3035420.9880.0890.3161.064100
3.84-4.0812.90.2175550.9890.0620.2261.019100
4.08-4.3912.50.165430.9950.0470.1671.04100
4.39-4.83120.1315560.9950.0390.1371.031100
4.83-5.5311.50.1265550.9950.0390.1320.922100
5.53-6.9510.10.1055730.9940.0340.1110.88699.8
6.95-308.40.0576230.9960.0220.0620.72499

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Processing

Software
NameVersionClassification
HKL-3000data scaling
PHENIX1.13_2998refinement
PDB_EXTRACT3.24data extraction
HKL-3000data reduction
PHASERphasing
REFMAC5.8.0230refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6ACM

6acm
PDB Unreleased entry


Resolution: 2.577→29.602 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 22.19
RfactorNum. reflection% reflection
Rfree0.2167 477 4.68 %
Rwork0.1842 --
obs0.1857 10192 93.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 103.76 Å2 / Biso mean: 41.8237 Å2 / Biso min: 16.93 Å2
Refinement stepCycle: final / Resolution: 2.577→29.602 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2019 0 26 41 2086
Biso mean--39.63 41.21 -
Num. residues----253
LS refinement shellResolution: 2.577→2.669 Å
RfactorNum. reflection% reflection
Rfree0.2551 34 -
Rwork0.2035 688 -
obs-722 67.92 %
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)
11.44560.50550.22531.9885-0.20161.4879-0.04170.0114-0.0010.10030.00710.01450.0933-0.00310.00590.2276-0.0617-0.01380.20220.02560.2117-34.492616.7327.7578
25.6759-1.37073.69095.0393-1.09977.42450.23820.4151-0.2968-0.48760.2292-0.21540.18160.8499-0.23310.3647-0.02690.12780.35120.16310.5564-26.6649-0.5446-0.591
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resseq 211:459)A211 - 459
2X-RAY DIFFRACTION2(chain C and resseq 741:751)C741 - 751

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