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- PDB-7wmo: A novel chemical derivative(92) of THRB agonist -

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Basic information

Entry
Database: PDB / ID: 7wmo
TitleA novel chemical derivative(92) of THRB agonist
Components
  • Isoform Beta-2 of Thyroid hormone receptor beta
  • Nuclear receptor coactivator 2
KeywordsTRANSCRIPTION / Transcription factor / ligand
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 / 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
Similarity search - Domain/homology
Chem-9IW / Thyroid hormone receptor beta / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.56 Å
AuthorsYao, B.Q. / Li, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31770814 China
Citation
Journal: J.Med.Chem. / Year: 2022
Title: Discovery of a Highly Selective and H435R-Sensitive Thyroid Hormone Receptor beta Agonist.
Authors: Li, Q. / Yao, B. / Zhao, S. / Lu, Z. / Zhang, Y. / Xiang, Q. / Wu, X. / Yu, H. / Zhang, C. / Li, J. / Zhuang, X. / Wu, D. / Li, Y. / Xu, Y.
#1: 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.
History
DepositionJan 15, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 18, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 8, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform Beta-2 of Thyroid hormone receptor beta
B: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,3233
Polymers30,7612
Non-polymers5631
Water1,17165
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1020 Å2
ΔGint-6 kcal/mol
Surface area11570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)106.558, 106.558, 56.681
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-642-

HOH

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Components

#1: Protein Isoform Beta-2 of Thyroid hormone receptor beta


Mass: 29410.996 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: THRB / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P10828
#2: Protein/peptide Nuclear receptor coactivator 2


Mass: 1349.576 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SRC2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q15596
#3: Chemical ChemComp-9IW / 2-[[1-ethoxy-7-[4-(3-fluoranyl-5-methoxy-phenyl)carbonyl-2,6-dimethyl-phenoxy]-4-oxidanyl-isoquinolin-3-yl]carbonylamino]ethanoic acid


Mass: 562.542 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H27FN2O8 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 65 / 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: 2.62 Å3/Da / Density % sol: 52.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.2 M sodium malonate pH 6.0 and 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 9, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.56→50 Å / Num. obs: 11022 / % possible obs: 100 % / Redundancy: 12.2 % / Rmerge(I) obs: 0.14 / Rpim(I) all: 0.042 / Rrim(I) all: 0.146 / Χ2: 0.965 / Net I/σ(I): 5.8 / Num. measured all: 133984
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2
2.56-2.610.61.4065370.6580.4441.4760.844
2.6-2.6511.51.1565260.7570.3521.2090.87
2.65-2.7121.0445450.7430.3131.090.879
2.7-2.7612.10.8425340.8440.2510.880.912
2.76-2.8211.90.6795430.8990.2040.710.932
2.82-2.88120.5865360.9510.1750.6120.952
2.88-2.9613.20.4895430.9640.140.5090.965
2.96-3.0413.10.4155420.9580.1190.4321.011
3.04-3.1213.10.3445260.9680.0980.3591.025
3.12-3.2312.70.2875510.9790.0840.2991.061
3.23-3.3412.30.2265560.9840.0670.2361.063
3.34-3.47120.1935210.9820.0580.2021.133
3.47-3.6312.40.175560.9870.050.1771.141
3.63-3.8212.90.1535540.9920.0440.1591.085
3.82-4.0612.70.145520.9930.0410.1461.068
4.06-4.3812.30.1275550.9930.0380.1330.991
4.38-4.8211.90.1175600.990.0350.1220.916
4.82-5.5112.70.1175640.9910.0340.1220.881
5.51-6.9411.60.1095820.9920.0330.1140.769
6.94-5010.40.0996390.9910.0320.1050.754

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
HKL-2000data scaling
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6KKB

6kkb


Resolution: 2.56→47.7 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.911 / SU B: 20.202 / SU ML: 0.216 / SU R Cruickshank DPI: 0.5442 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.544 / ESU R Free: 0.28 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2407 518 4.8 %RANDOM
Rwork0.2149 ---
obs0.2162 10234 97.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 138.32 Å2 / Biso mean: 42.44 Å2 / Biso min: 15.94 Å2
Baniso -1Baniso -2Baniso -3
1--0.79 Å20 Å20 Å2
2---0.79 Å20 Å2
3---1.58 Å2
Refinement stepCycle: final / Resolution: 2.56→47.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1912 0 41 65 2018
Biso mean--55.33 36.75 -
Num. residues----240
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0131998
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171909
X-RAY DIFFRACTIONr_angle_refined_deg1.381.6422703
X-RAY DIFFRACTIONr_angle_other_deg1.2241.5764400
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3485236
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.0221.97996
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.61715350
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.5991511
X-RAY DIFFRACTIONr_chiral_restr0.0630.2255
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022181
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02438
LS refinement shellResolution: 2.56→2.625 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.315 26 -
Rwork0.332 563 -
obs--74.94 %
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)
11.8659-0.52890.53731.1472-0.7691.409-0.0405-0.01720.01060.0369-0.0577-0.0136-0.0847-0.13940.09820.20740.11650.05350.1478-0.01130.039417.730835.1273-7.7301
28.1049-0.41761.497811.4-5.964211.69270.13380.0477-0.0972-0.3888-0.20920.12070.243-0.05030.07540.09710.00870.05490.1083-0.07760.10170.373126.7627-13.7732
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A210 - 459
2X-RAY DIFFRACTION2B741 - 751

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