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- PDB-7wlx: A novel chemical derivative(53) of THRB agonist -

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Basic information

Entry
Database: PDB / ID: 7wlx
TitleA novel chemical derivative(53) 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 / retinal cone cell development / thyroid hormone mediated signaling pathway / positive regulation of thyroid hormone mediated signaling pathway / cellular response to thyroid hormone stimulus / regulation of heart contraction / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / type I pneumocyte differentiation ...retinal cone cell apoptotic process / negative regulation of female receptivity / female courtship behavior / retinal cone cell development / thyroid hormone mediated signaling pathway / positive regulation of thyroid hormone mediated signaling pathway / cellular response to thyroid hormone stimulus / regulation of heart contraction / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / type I pneumocyte differentiation / thyroid hormone binding / locomotor rhythm / aryl hydrocarbon receptor binding / regulation of lipid metabolic process / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / retinoic acid receptor signaling pathway / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Recycling of bile acids and salts / regulation of cellular response to insulin stimulus / cellular response to hormone stimulus / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / Regulation of lipid metabolism by PPARalpha / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / Activation of gene expression by SREBF (SREBP) / response to progesterone / nuclear receptor binding / sensory perception of sound / circadian regulation of gene expression / SUMOylation of intracellular receptors / Heme signaling / mRNA transcription by RNA polymerase II / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Transcriptional activation of mitochondrial biogenesis / transcription coactivator binding / PPARA activates gene expression / Cytoprotection by HMOX1 / chromatin DNA binding / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / nuclear receptor activity / Circadian Clock / sequence-specific double-stranded DNA binding / HATs acetylate histones / Estrogen-dependent gene expression / transcription regulator complex / cell differentiation / transcription coactivator activity / protein dimerization activity / nuclear body / DNA-binding transcription factor activity, RNA polymerase II-specific / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein domain specific binding / DNA-templated transcription / chromatin binding / chromatin / regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / enzyme binding / 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 / PAS domain / Nuclear receptor coactivator, interlocking / Helix-loop-helix DNA-binding domain superfamily / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / 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 / Zinc finger, C4 type (two domains) / 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-9GC / Thyroid hormone receptor beta / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.39 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 14, 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)31,2193
Polymers30,7612
Non-polymers4581
Water1,18966
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 area11590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)105.898, 105.898, 57.105
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-655-

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-9GC / 2-[[1-methoxy-4-oxidanyl-7-[4-(phenylmethyl)phenoxy]isoquinolin-3-yl]carbonylamino]ethanoic acid


Mass: 458.463 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H22N2O6 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 66 / 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: 2.6 Å3/Da / Density % sol: 52.73 %
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 and 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: BL19U1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Nov 22, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.39→50 Å / Num. obs: 13381 / % possible obs: 100 % / Redundancy: 12.5 % / Rmerge(I) obs: 0.041 / Rpim(I) all: 0.013 / Rrim(I) all: 0.043 / Χ2: 0.917 / Net I/σ(I): 14.1 / Num. measured all: 167276
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.39-2.4312.30.4776430.9590.140.4980.86999.7
2.43-2.4813.30.4036600.9740.1140.4190.88100
2.48-2.5213.20.3646490.9860.1040.3790.95100
2.52-2.5713.30.2686480.990.0760.2790.922100
2.57-2.6312.90.2326530.9890.0670.2420.893100
2.63-2.6912.80.2046460.9950.0590.2121.063100
2.69-2.7612.40.1586610.9940.0460.1650.981100
2.76-2.8311.60.1326640.9960.040.1381.063100
2.83-2.9213.20.1066470.9960.030.110.996100
2.92-3.0113.20.0886800.9980.0250.0920.919100
3.01-3.1213.10.076470.9980.020.0730.893100
3.12-3.2412.80.0566700.9990.0160.0590.878100
3.24-3.3912.10.0456620.9990.0140.0470.86100
3.39-3.5711.80.0416670.9990.0120.0420.925100
3.57-3.7912.90.0396730.9990.0110.0410.922100
3.79-4.0912.60.0356740.9990.010.0370.93299.9
4.09-4.5120.0326750.9990.010.0330.83100
4.5-5.1512.40.0316960.9990.0090.0330.802100
5.15-6.48120.0327000.9990.0090.0330.781100
6.48-5010.40.0357660.9990.0110.0370.98699.9

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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: 2.39→47.4 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.871 / SU B: 15.225 / SU ML: 0.18 / SU R Cruickshank DPI: 0.3726 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.373 / ESU R Free: 0.267 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2697 617 4.7 %RANDOM
Rwork0.2206 ---
obs0.223 12399 97.43 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 123.12 Å2 / Biso mean: 43.462 Å2 / Biso min: 10.67 Å2
Baniso -1Baniso -2Baniso -3
1--0.23 Å20 Å2-0 Å2
2---0.23 Å2-0 Å2
3---0.46 Å2
Refinement stepCycle: final / Resolution: 2.39→47.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1931 0 34 66 2031
Biso mean--42.49 37.93 -
Num. residues----241
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0132010
X-RAY DIFFRACTIONr_bond_other_d0.0020.0151929
X-RAY DIFFRACTIONr_angle_refined_deg1.3941.6422715
X-RAY DIFFRACTIONr_angle_other_deg1.3861.5774453
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5765237
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.92222.14398
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.03215359
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.11511
X-RAY DIFFRACTIONr_chiral_restr0.0720.2256
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022188
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02443
LS refinement shellResolution: 2.39→2.452 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.234 34 -
Rwork0.225 725 -
all-759 -
obs--79.48 %
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)
12.4498-1.337-0.12822.0240.43811.36350.03870.0417-0.1586-0.0433-0.2455-0.01340.0230.17060.20680.11270.0375-0.03110.12310.07290.0889-17.0286-34.3973-7.7326
27.58333.3084-0.46498.21833.7412.3267-0.0520.34170.2688-0.27150.1613-0.0714-0.15020.0011-0.10930.0401-0.0443-0.05980.09910.11790.16460.1844-26.4721-14.456
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A211 - 459
2X-RAY DIFFRACTION2B741 - 751

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