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

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Basic information

Entry
Database: PDB / ID: 6knu
TitleTHRb mutation with a novel agonist
Components
  • Nuclear receptor coactivator 2
  • 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 receptor signaling pathway / positive regulation of thyroid hormone receptor signaling pathway / cellular response to thyroid hormone stimulus / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / regulation of heart contraction / type I pneumocyte differentiation ...retinal cone cell apoptotic process / negative regulation of female receptivity / female courtship behavior / retinal cone cell development / thyroid hormone receptor signaling pathway / positive regulation of thyroid hormone receptor signaling pathway / cellular response to thyroid hormone stimulus / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / regulation of heart contraction / 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 / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / retinoic acid receptor signaling pathway / 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 / regulation of cellular response to insulin stimulus / BMAL1:CLOCK,NPAS2 activates circadian gene expression / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / 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 / PPARA activates gene expression / Cytoprotection by HMOX1 / chromatin DNA binding / transcription coactivator 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 / HATs acetylate histones / Estrogen-dependent gene expression / transcription regulator complex / transcription coactivator activity / cell differentiation / protein dimerization activity / DNA-binding transcription factor activity, RNA polymerase II-specific / nuclear body / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein domain specific binding / DNA-templated transcription / chromatin binding / regulation of DNA-templated transcription / chromatin / 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 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-8HO / Thyroid hormone receptor beta / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 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
DepositionAug 7, 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

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Assembly

Deposited unit
A: Thyroid hormone receptor beta
C: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,9903
Polymers29,6372
Non-polymers3521
Water1,00956
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area990 Å2
ΔGint-9 kcal/mol
Surface area12000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.834, 109.834, 57.524
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: 28287.754 Da / Num. of mol.: 1 / Mutation: V264D
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 Nuclear receptor coactivator 2 / NCoA-2 / Class E basic helix-loop-helix protein 75 / bHLHe75 / Transcriptional intermediary factor 2 / hTIF2


Mass: 1349.576 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NCOA2, BHLHE75, SRC2, TIF2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q15596
#3: Chemical ChemComp-8HO / 2-[(1-methyl-4-oxidanyl-7-phenoxy-isoquinolin-3-yl)carbonylamino]ethanoic acid


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


Mass: 18.015 Da / Num. of mol.: 56 / 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: 3.03 Å3/Da / Density % sol: 59.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 0.1M Sodium acetate trihydrate pH 4.6, 2.0M Sodium formate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / 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: 2.7→49.12 Å / Num. obs: 9693 / % possible obs: 95.1 % / Redundancy: 12.6 % / Biso Wilson estimate: 44.59 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.137 / Rpim(I) all: 0.041 / Rrim(I) all: 0.143 / Net I/σ(I): 15.2 / Num. measured all: 170587 / Scaling rejects: 962
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.7-3.111.91.2012408020280.7290.3631.2562.999.9
7.6-49.1211.10.0759225350.9950.0220.07430.199.7

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
Aimless0.6.2data scaling
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6ACM

6acm
PDB Unreleased entry


Resolution: 2.7→49.119 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 24.34 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2312 458 4.73 %RANDOM
Rwork0.1773 9235 --
obs0.1798 9693 95.77 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 201.88 Å2 / Biso mean: 61.3045 Å2 / Biso min: 13.21 Å2
Refinement stepCycle: final / Resolution: 2.7→49.119 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2004 0 26 56 2086
Biso mean--47.83 49.72 -
Num. residues----251
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.7-3.09050.27981540.16993124100
3.0905-3.89340.29271420.2039282590
3.8934-49.1190.19231620.16773286100
Refinement TLS params.Method: refined / Origin x: 18.6358 Å / Origin y: 37.2869 Å / Origin z: 5.798 Å
111213212223313233
T0.1925 Å20.054 Å2-0.0069 Å2-0.1154 Å20.0248 Å2--0.1452 Å2
L1.1267 °2-0.0218 °2-0.9019 °2-0.9987 °2-0.079 °2--0.9492 °2
S0.082 Å °0.0107 Å °-0.0979 Å °-0.054 Å °-0.0658 Å °0.022 Å °-0.1463 Å °-0.0784 Å °0.0017 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA211 - 460
2X-RAY DIFFRACTION1allA501 - 656
3X-RAY DIFFRACTION1allC741 - 749

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