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- PDB-9ix5: An agonist(compound 15n) of Thyroid Hormone Receptor B -

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Basic information

Entry
Database: PDB / ID: 9ix5
TitleAn agonist(compound 15n) of Thyroid Hormone Receptor B
Components
  • Nuclear receptor coactivator 2
  • Thyroid hormone receptor beta
KeywordsTRANSCRIPTION / Nuclear receptor ligand-binding domain / agonist
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 / type I pneumocyte differentiation ...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 / type I pneumocyte differentiation / regulation of heart contraction / 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 / transcription regulator inhibitor activity / retinoic acid receptor signaling pathway / cellular response to hormone stimulus / Recycling of bile acids and salts / 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 / sensory perception of sound / circadian regulation of gene expression / mRNA transcription by RNA polymerase II / Heme signaling / Transcriptional activation of mitochondrial biogenesis / transcription coactivator binding / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / PPARA activates gene expression / Cytoprotection by HMOX1 / Nuclear Receptor transcription pathway / chromatin DNA binding / Transcriptional regulation of white adipocyte differentiation / 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 / cell differentiation / transcription coactivator activity / DNA-binding transcription factor activity, RNA polymerase II-specific / protein dimerization activity / nuclear body / protein domain specific binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / 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
: / Thyroid hormone receptor beta / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 Å
AuthorsYao, B. / Li, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82173745 China
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of a Potent, Selective, and Multiple His435 Mutation-Sensitive Thyroid Hormone Receptor beta Agonist.
Authors: Li, Q. / Yao, B. / Zhao, S. / Lu, Z. / Wu, X. / Lu, Z. / Wu, T. / Li, J. / Chen, X. / Chen, Z. / Zhang, C. / Wu, D. / Zhang, Y. / Xiang, Q. / Li, Y. / Xu, Y.
History
DepositionJul 26, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 2, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Thyroid hormone receptor beta
B: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,1653
Polymers30,7472
Non-polymers4181
Water1,51384
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1090 Å2
ΔGint-6 kcal/mol
Surface area11130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)107.577, 107.577, 57.103
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 29281.887 Da / Num. of mol.: 1
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) / 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: 1464.664 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) / References: UniProt: Q15596
#3: Chemical ChemComp-A1EAC / 2-[(1-methoxy-7-naphthalen-2-yloxy-4-oxidanyl-isoquinolin-3-yl)carbonylamino]ethanoic acid


Mass: 418.399 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H18N2O6 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 84 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.69 Å3/Da / Density % sol: 54.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.35 M Sodium citrate tribasic dihydrate, 22%(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: STFC Large Pixel Detector / Detector: PIXEL / Date: Mar 21, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.64→50 Å / Num. obs: 10344 / % possible obs: 100 % / Redundancy: 12.4 % / CC1/2: 1 / CC star: 1 / Rmerge(I) obs: 0.034 / Rpim(I) all: 0.01 / Rrim(I) all: 0.036 / Χ2: 0.942 / Net I/σ(I): 12.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
2.64-2.6912.70.8284970.840.9550.240.8630.979100
2.69-2.7312.21.4085040.810.9460.4181.470.867100
2.73-2.7911.50.7944930.8440.9570.2430.8310.869100
2.79-2.8411.90.6175210.9310.9820.1860.6450.875100
2.84-2.9113.10.5045090.9520.9880.1450.5250.894100
2.91-2.9713.30.4075010.9620.990.1160.4240.895100
2.97-3.0513.20.2975070.9840.9960.0840.3090.894100
3.05-3.1313.30.2365070.9860.9970.0670.2450.97100
3.13-3.22130.1844950.9940.9980.0530.1910.957100
3.22-3.33130.1265120.9950.9990.0360.1310.962100
3.33-3.4412.70.115080.9970.9990.0320.1141.161100
3.44-3.58120.0775230.99810.0230.081.105100
3.58-3.7511.20.0834990.9970.9990.0270.0881.177100
3.75-3.9412.70.0595230.99810.0170.0610.99100
3.94-4.1913.20.0395160.99910.0110.040.833100
4.19-4.5112.90.0315290.99910.0090.0330.94100
4.51-4.9712.50.028515110.0080.030.904100
4.97-5.6911.20.0255400.99910.0080.0261.028100
5.69-7.1612.60.021550110.0060.0220.746100
7.16-5010.70.019595110.0060.020.8499.8

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Processing

Software
NameVersionClassification
PHENIX(1.18.2_3874: ???)refinement
HKL-3000data reduction
HKL-3000data scaling
HKL-3000phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.65→48.11 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 25.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2766 483 5 %
Rwork0.2287 --
obs0.231 9669 94.54 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.65→48.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1900 0 31 84 2015
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0041973
X-RAY DIFFRACTIONf_angle_d0.8172665
X-RAY DIFFRACTIONf_dihedral_angle_d5.97278
X-RAY DIFFRACTIONf_chiral_restr0.046300
X-RAY DIFFRACTIONf_plane_restr0.004332
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.65-3.030.32381500.25982693X-RAY DIFFRACTION86
3.03-3.820.32061630.24073171X-RAY DIFFRACTION99
3.82-48.110.23171700.21033322X-RAY DIFFRACTION99
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)
10.23940.0394-0.07860.11260.00850.0734-0.2857-0.0822-0.2675-0.09380.1256-0.00460.08180.1073-0.23650.09140.23730.04480.0767-0.05850.1245-17.7619-35.1921-7.447
20.0007-0.00020.00070.00080.00030.00120.00630.00520.01180.00510.01310.0049-0.01760.002500.2977-0.0436-0.03860.35150.0030.3629-0.2987-27.1456-14.1523
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resseq 211:459)
2X-RAY DIFFRACTION2(chain B and resseq 741:751)

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