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- PDB-7wmn: A novel chemical derivative(89) of THRB agonist -

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Basic information

Entry
Database: PDB / ID: 7wmn
TitleA novel chemical derivative(89) 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 / female courtship behavior / negative regulation of female receptivity / 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 / locomotor rhythm ...retinal cone cell apoptotic process / female courtship behavior / negative regulation of female receptivity / 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 / locomotor rhythm / regulation of heart contraction / type I pneumocyte differentiation / aryl hydrocarbon receptor binding / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / regulation of lipid metabolic process / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression / Expression of BMAL (ARNTL), CLOCK, and NPAS2 / Recycling of bile acids and salts / transcription regulator inhibitor activity / retinoic acid receptor signaling pathway / cellular response to hormone stimulus / 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 / response to progesterone / Activation of gene expression by SREBF (SREBP) / nuclear receptor binding / negative regulation of smoothened signaling pathway / SUMOylation of intracellular receptors / circadian regulation of gene expression / Heme signaling / sensory perception of sound / PPARA activates gene expression / Transcriptional activation of mitochondrial biogenesis / 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 / mRNA transcription by RNA polymerase II / RNA polymerase II transcription regulator complex / transcription coactivator binding / 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 / transcription coactivator activity / cell differentiation / protein dimerization activity / nuclear body / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein domain specific binding / chromatin binding / DNA-templated transcription / 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-9IT / Thyroid hormone receptor beta / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.57 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)31,2753
Polymers30,7612
Non-polymers5151
Water84747
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1020 Å2
ΔGint-5 kcal/mol
Surface area12030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)106.234, 106.234, 56.866
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 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-9IT / 2-[[7-[2,6-dimethyl-4-(3-methylphenyl)carbonyl-phenoxy]-1-methoxy-4-oxidanyl-isoquinolin-3-yl]carbonylamino]ethanoic acid


Mass: 514.526 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H26N2O7 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 47 / 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: 2.61 Å3/Da / Density % sol: 52.84 %
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: 2.57→50 Å / Num. obs: 10838 / % possible obs: 100 % / Redundancy: 12.2 % / Rmerge(I) obs: 0.096 / Rpim(I) all: 0.03 / Rrim(I) all: 0.101 / Χ2: 0.941 / Net I/σ(I): 7.6 / Num. measured all: 132453
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.57-2.6111.61.4825320.6090.4531.5510.858100
2.61-2.66131.2395110.7820.3561.290.926100
2.66-2.7112.81.0415360.760.3011.0850.92499.8
2.71-2.77130.7625280.8770.2190.7930.916100
2.77-2.8312.80.5975290.9430.1730.6220.929100
2.83-2.8912.60.5295260.9550.1540.5520.921100
2.89-2.9712.50.4335290.9630.1280.4520.946100
2.97-3.05120.3635360.970.1090.3791.069100
3.05-3.1411.80.2865380.9780.0860.2990.987100
3.14-3.2412.10.2225190.9870.0660.2310.996100
3.24-3.3512.90.1675460.9930.0480.1741.024100
3.35-3.4912.90.1315360.9930.0380.1361.059100
3.49-3.6512.70.1115440.9950.0330.1161.017100
3.65-3.8412.30.0955270.9950.0280.0991.035100
3.84-4.0811.60.0825480.9970.0250.0860.978100
4.08-4.3912.10.0745460.9970.0220.0770.894100
4.39-4.8412.60.0695520.9970.020.0720.83100
4.84-5.5312.20.0685600.9960.020.0710.788100
5.53-6.9711.40.0685710.9970.0210.0720.796100
6.97-509.90.0716240.9960.0240.0750.93899.8

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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: 2.57→47.55 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.897 / SU B: 21.957 / SU ML: 0.237 / SU R Cruickshank DPI: 0.6347 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.635 / ESU R Free: 0.316 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.261 499 4.8 %RANDOM
Rwork0.2152 ---
obs0.2175 9793 95.29 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 128.79 Å2 / Biso mean: 47.174 Å2 / Biso min: 20.2 Å2
Baniso -1Baniso -2Baniso -3
1--0.57 Å20 Å20 Å2
2---0.57 Å20 Å2
3---1.14 Å2
Refinement stepCycle: final / Resolution: 2.57→47.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1950 0 38 47 2035
Biso mean--69.01 37.34 -
Num. residues----243
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0132034
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171945
X-RAY DIFFRACTIONr_angle_refined_deg1.4571.6412750
X-RAY DIFFRACTIONr_angle_other_deg1.3751.5774489
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3195239
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.99122.2100
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.51415362
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.1441511
X-RAY DIFFRACTIONr_chiral_restr0.0750.2258
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022219
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02444
LS refinement shellResolution: 2.573→2.64 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.253 10 -
Rwork0.275 335 -
all-345 -
obs--44.57 %
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)
11.9322-0.7583-0.24071.47420.79721.37790.0193-0.017-0.0660.0053-0.10870.02960.02640.1470.08940.1620.0902-0.04240.14780.0240.0416-17.3786-34.7832-7.5864
27.3188-0.74990.37097.77535.27938.06570.0081-0.06590.0205-0.25930.13670.3687-0.25190.2937-0.14480.0144-0.0206-0.01680.09090.05170.1084-0.0743-26.6192-14.0599
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A210 - 459
2X-RAY DIFFRACTION2B741 - 751

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