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- PDB-7wml: A novel chemical derivative(85) of THRB agonist -

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Basic information

Entry
Database: PDB / ID: 7wml
TitleA novel chemical derivative(85) 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 / type I pneumocyte differentiation / locomotor rhythm / 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 / cellular response to hormone stimulus / Recycling of bile acids and salts / 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 / Cytoprotection by HMOX1 / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / 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-9IQ / 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 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
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)31,3033
Polymers30,7612
Non-polymers5431
Water73941
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 area11800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)107.810, 107.810, 57.510
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-641-

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-9IQ / 2-[[7-[4-(3,5-dimethylphenyl)carbonyl-2,6-dimethyl-phenoxy]-1-ethoxy-4-oxidanyl-isoquinolin-3-yl]carbonylamino]ethanoic acid


Mass: 542.579 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H30N2O7 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 41 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.72 Å3/Da / Density % sol: 54.72 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1 M MgSO4 and 12% PEG 6000.

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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 9, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.66→50 Å / Num. obs: 10251 / % possible obs: 100 % / Redundancy: 12.5 % / Rmerge(I) obs: 0.064 / Rpim(I) all: 0.02 / Rrim(I) all: 0.067 / Χ2: 0.863 / Net I/σ(I): 6.3 / Num. measured all: 127983
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.66-2.7112.51.9415000.8950.5892.0311.871100
2.71-2.7613.31.8385010.6890.5181.910.54100
2.76-2.8113.31.3044920.7640.3691.3560.543100
2.81-2.8713.20.884980.9110.2510.9150.528100
2.87-2.93130.7765000.9170.2230.8080.565100
2.93-312.80.695080.9240.20.7190.589100
3-3.0712.20.4665010.9630.1390.4870.6899.8
3.07-3.1512.40.3194950.9710.0930.3330.594100
3.15-3.2512.30.2475060.9870.0730.2580.638100
3.25-3.3513.40.195090.990.0540.1980.681100
3.35-3.4712.40.2154950.9790.0670.2261.515100
3.47-3.61130.1185190.9950.0340.1220.924100
3.61-3.7712.30.1354970.9930.0410.1421.456100
3.77-3.9711.70.1025170.9920.0320.1071.496100
3.97-4.2211.90.0625110.9970.0190.0650.913100
4.22-4.5512.90.0535170.9990.0150.0550.868100
4.55-5130.0495160.9980.0140.0510.836100
5-5.7312.20.0475330.9990.0140.0490.733100
5.73-7.2111.80.0445500.9980.0130.0460.653100
7.21-5010.50.0385860.9990.0120.040.769100

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Processing

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

6kkb


Resolution: 2.67→48.26 Å / Cor.coef. Fo:Fc: 0.91 / Cor.coef. Fo:Fc free: 0.898 / SU B: 26.006 / SU ML: 0.249 / SU R Cruickshank DPI: 1.1482 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.148 / ESU R Free: 0.334 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2451 445 4.9 %RANDOM
Rwork0.2193 ---
obs0.2205 8567 89.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 139.33 Å2 / Biso mean: 46.083 Å2 / Biso min: 8.31 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å20 Å20 Å2
2---0.01 Å2-0 Å2
3---0.02 Å2
Refinement stepCycle: final / Resolution: 2.67→48.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1916 0 40 41 1997
Biso mean--67.23 34.28 -
Num. residues----239
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0131999
X-RAY DIFFRACTIONr_bond_other_d0.0030.0151933
X-RAY DIFFRACTIONr_angle_refined_deg1.5171.6422701
X-RAY DIFFRACTIONr_angle_other_deg1.5151.5784457
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3335234
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.08122.16597
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.52915357
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1231511
X-RAY DIFFRACTIONr_chiral_restr0.0680.2254
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022168
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02435
LS refinement shellResolution: 2.671→2.741 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.19 2 -
Rwork0.367 27 -
all-29 -
obs--3.99 %
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)
12.2466-0.8945-0.00312.11840.33141.1724-0.0412-0.0273-0.0968-0.0343-0.0892-0.1075-0.03780.13820.13050.07840.0602-0.01820.07720.01550.044-17.7954-35.3546-7.3824
21.86373.76382.17748.17676.05729.8314-0.0690.07770.29780.0093-0.02290.52960.1390.35860.09190.0582-0.114-0.01550.30610.0170.1845-0.4784-27.3979-13.7278
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A211 - 459
2X-RAY DIFFRACTION2B741 - 751

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