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

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Basic information

Entry
Database: PDB / ID: 6knv
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 / thyroid hormone binding / 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 ...retinal cone cell apoptotic process / negative regulation of female receptivity / female courtship behavior / thyroid hormone binding / 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 / locomotor rhythm / type I pneumocyte differentiation / 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 / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Recycling of bile acids and salts / cellular response to hormone stimulus / transcription regulator inhibitor activity / retinoic acid receptor signaling pathway / : / positive regulation of adipose tissue development / Regulation of lipid metabolism by PPARalpha / 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 / nuclear receptor binding / negative regulation of smoothened signaling pathway / SUMOylation of intracellular receptors / circadian regulation of gene expression / mRNA transcription by RNA polymerase II / Heme signaling / sensory perception of sound / 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 / chromatin DNA binding / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / transcription coactivator binding / 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 / transcription regulator complex / Estrogen-dependent gene expression / DNA-binding transcription factor activity, RNA polymerase II-specific / cell differentiation / transcription coactivator activity / protein dimerization activity / nuclear body / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein domain specific binding / DNA-templated transcription / chromatin binding / regulation of DNA-templated transcription / chromatin / enzyme binding / 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
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 / 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 / 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 / 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 / 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: 2.8 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

Downloads & links

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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)30,0033
Polymers29,6502
Non-polymers3521
Water1,08160
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1000 Å2
ΔGint-6 kcal/mol
Surface area11750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)106.151, 106.151, 56.624
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: 28300.812 Da / Num. of mol.: 1 / Mutation: R438W
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
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 60 / 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: 2.84 Å3/Da / Density % sol: 56.73 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 2% v/v Tacsimate pH 5.0, 0.1 M Sodium citrate tribasic dihydrate pH 5.6, 16% 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: BL17U1 / 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: 1.97→50 Å / Num. obs: 10613 / % possible obs: 91.6 % / Redundancy: 2.9 % / Rmerge(I) obs: 0.25 / Rpim(I) all: 0.162 / Rrim(I) all: 0.292 / Χ2: 0.696 / Net I/σ(I): 3.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Num. unique obsCC1/2Χ2% possible allRmerge(I) obsRpim(I) allRrim(I) all
1.97-21.88990.0580.47879.6
2-2.0429190.0710.55581.48.0546.259
2.04-2.082.19520.0020.84584.83.1622.4194.008
2.08-2.122.29990.51587.67.0185.2868.847
2.12-2.172.310490.0420.45593.2
2.17-2.222.510600.0420.64893.6
2.22-2.272.510550.1490.85934.2873.1485.357
2.27-2.342.710960.0460.50396.66.5774.6038.079
2.34-2.42.810600.0030.52393.65.9664.1957.342
2.4-2.482.610250.0150.49489.45.0183.4546.137
2.48-2.572.810740.0350.51193.13.0352.033.676
2.57-2.673.310900.2770.64197.52.0921.3552.51
2.67-2.83.411130.1540.53496.31.6531.0311.96
2.8-2.943.511050.3060.53495.81.2420.7371.454
2.94-3.133.611030.4680.667960.9870.5631.143
3.13-3.373.511190.6860.65496.10.570.3310.665
3.37-3.713.110700.8081.14891.60.3570.2150.419
3.71-4.243.611300.9281.07195.50.2250.1280.26
4.24-5.353.311160.960.9892.80.1250.0760.147
5.35-502.911040.9780.84785.20.0880.0620.109

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
HKL-2000data scaling
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHASERphasing
REFMAC5.8.0230refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6ACM

6acm
PDB Unreleased entry


Resolution: 2.8→47.472 Å / SU ML: 0.41 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 29.75
RfactorNum. reflection% reflection
Rfree0.2648 397 5.2 %
Rwork0.1939 --
obs0.1976 7635 91.06 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 116.44 Å2 / Biso mean: 53.2249 Å2 / Biso min: 24.41 Å2
Refinement stepCycle: final / Resolution: 2.8→47.472 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1957 0 26 60 2043
Biso mean--52.33 52.52 -
Num. residues----246
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.90010.3632450.2525672X-RAY DIFFRACTION90
2.9001-3.01620.3532480.2279715X-RAY DIFFRACTION92
3.0162-3.15340.3117380.2068729X-RAY DIFFRACTION94
3.1534-3.31960.3098420.2218745X-RAY DIFFRACTION96
3.3196-3.52760.2474400.1888721X-RAY DIFFRACTION92
3.5276-3.79980.2725390.1774706X-RAY DIFFRACTION90
3.7998-4.1820.2283390.1796751X-RAY DIFFRACTION95
4.182-4.78670.2849330.1688746X-RAY DIFFRACTION92
4.7867-6.02870.2365330.1984766X-RAY DIFFRACTION93
Refinement TLS params.Method: refined / Origin x: 34.2191 Å / Origin y: -15.8264 Å / Origin z: 7.0722 Å
111213212223313233
T0.3148 Å2-0.09 Å2-0.048 Å2-0.2957 Å2-0.0283 Å2--0.3129 Å2
L1.8284 °20.0049 °2-0.7192 °2-2.334 °2-0.242 °2--1.5211 °2
S-0.0545 Å °0.1007 Å °-0.0986 Å °0.0977 Å °0.028 Å °-0.0092 Å °0.0238 Å °-0.1153 Å °0.0589 Å °
Refinement TLS groupSelection details: (chain A and resseq 211:459)

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