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

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Basic information

Entry
Database: PDB / ID: 6knw
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: 2.67 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)29,9553
Polymers29,6022
Non-polymers3521
Water66737
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area980 Å2
ΔGint-8 kcal/mol
Surface area11880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)106.301, 106.301, 57.353
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: 28252.748 Da / Num. of mol.: 1 / Mutation: R438H
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.: 37 / 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: 2.81 Å3/Da / Density % sol: 56.2 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 100mM Nacl 20% PEG 4000

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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: Jun 30, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.666→50 Å / Num. obs: 9857 / % possible obs: 100 % / Redundancy: 23.7 % / Rmerge(I) obs: 0.08 / Rpim(I) all: 0.018 / Rrim(I) all: 0.082 / Χ2: 0.959 / Net I/σ(I): 11.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.67-2.7225.10.554780.9820.1120.5620.844100
2.72-2.7723.90.4334690.9870.0890.4420.859100
2.77-2.8224.70.3734880.9890.0760.3810.836100
2.82-2.8824.40.2974950.9950.0610.3030.864100
2.88-2.9426.40.2624730.9950.0520.2680.863100
2.94-3.0126.50.2374830.9950.0470.2420.91100
3.01-3.0826.30.2094720.9970.0420.2130.948100
3.08-3.1725.80.1694790.9960.0340.1720.963100
3.17-3.2625.80.1584910.9960.0320.1611.047100
3.26-3.3625.40.1264850.9960.0260.1291.064100
3.36-3.4824.10.1044820.9970.0220.1071.141100
3.48-3.6222.50.0924940.9960.020.0951.148100
3.62-3.79230.0864850.9980.0190.0881.187100
3.79-3.9924.80.0784840.9980.0160.081.148100
3.99-4.2424.90.0735030.9980.0150.0751.15100
4.24-4.5624.20.0684940.9990.0140.071.103100
4.56-5.0222.90.0635000.9980.0140.0650.967100
5.02-5.7520.90.0595190.9980.0130.060.828100
5.75-7.2422.30.0495140.9990.0110.0510.635100
7.24-5012.80.0395690.9980.0130.0410.45199.3

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Processing

Software
NameVersionClassification
PHENIX(1.14_3260: ???)refinement
HKL-3000data scaling
PDB_EXTRACT3.24data extraction
HKL-3000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6ACM

6acm
PDB Unreleased entry


Resolution: 2.67→38.984 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.4 / Phase error: 21.9
RfactorNum. reflection% reflectionSelection details
Rfree0.2442 489 4.98 %RANDOM
Rwork0.1664 ---
obs0.1702 9818 99.89 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 125.91 Å2 / Biso mean: 43.6021 Å2 / Biso min: 16.48 Å2
Refinement stepCycle: final / Resolution: 2.67→38.984 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2020 0 26 37 2083
Biso mean--35 41.45 -
Num. residues----253
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
2.6661-3.05170.28831580.18743041
3.0517-3.84430.27081640.17433061
3.8443-38.9840.21021670.15333227
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)
12.44790.183-0.36842.6969-0.30732.6014-0.0367-0.04390.06270.10450.1284-0.0895-0.17020.0518-0.07160.2103-0.1024-0.00820.2036-0.01780.221734.521-16.7657.79
25.10131.7012-0.17692.01530.73112.0180.22840.2449-0.0342-0.33210.13380.69090.1476-0.9576-0.33910.4598-0.0128-0.1020.4405-0.08080.670425.824-0.0480.259
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 211:460 OR RESID 501:501 OR RESID 601:637 ) )A211 - 460
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 211:460 OR RESID 501:501 OR RESID 601:637 ) )A501
3X-RAY DIFFRACTION1( CHAIN A AND ( RESID 211:460 OR RESID 501:501 OR RESID 601:637 ) )A601 - 637
4X-RAY DIFFRACTION2( CHAIN C AND RESID 741:750 )C741 - 750

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