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- PDB-8rqn: Human thyroid hormone receptor beta ligand binding domain in comp... -

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Basic information

Entry
Database: PDB / ID: 8rqn
TitleHuman thyroid hormone receptor beta ligand binding domain in complex with beta-selective agonist ALG-055009
ComponentsThyroid hormone receptor beta
KeywordsMEMBRANE PROTEIN / thyroid receptor beta / thyroid receptor alpha / nuclear receptors / thyroid receptor agonist / thyroid receptor ligand / structure-based drug design
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 receptor signaling pathway / positive regulation of thyroid hormone receptor signaling pathway / cellular response to thyroid hormone stimulus / regulation of heart contraction / type I pneumocyte differentiation / thyroid hormone binding ...retinal cone cell apoptotic process / negative regulation of female receptivity / female courtship behavior / retinal cone cell development / thyroid hormone receptor signaling pathway / positive regulation of thyroid hormone receptor signaling pathway / cellular response to thyroid hormone stimulus / regulation of heart contraction / type I pneumocyte differentiation / thyroid hormone binding / retinoic acid receptor signaling pathway / sensory perception of sound / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / chromatin DNA binding / transcription coactivator binding / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / nuclear receptor activity / sequence-specific double-stranded DNA binding / cell differentiation / nuclear body / DNA-binding transcription factor activity, RNA polymerase II-specific / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-templated transcription / chromatin / negative regulation of transcription by RNA polymerase II / enzyme binding / positive regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
Thyroid hormone receptor / : / 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 ...Thyroid hormone receptor / : / 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
: / Thyroid hormone receptor beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.88 Å
AuthorsLammens, A. / Maskos, K. / Stoycheva, A.D. / McGowan, D.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery and Preclinical Profile of ALG-055009, a Potent and Selective Thyroid Hormone Receptor Beta (THR-beta ) Agonist for the Treatment of MASH.
Authors: Vandyck, K. / McGowan, D.C. / Luong, X.G. / Stevens, S.K. / Jekle, A. / Gupta, K. / Misner, D.L. / Chanda, S. / Serebryany, V. / Welch, M. / Hu, H. / Lv, Z. / Williams, C. / Maskos, K. / ...Authors: Vandyck, K. / McGowan, D.C. / Luong, X.G. / Stevens, S.K. / Jekle, A. / Gupta, K. / Misner, D.L. / Chanda, S. / Serebryany, V. / Welch, M. / Hu, H. / Lv, Z. / Williams, C. / Maskos, K. / Lammens, A. / Stoycheva, A.D. / Lin, T.I. / Blatt, L.M. / Beigelman, L.N. / Symons, J.A. / Raboisson, P. / Deval, J.
History
DepositionJan 18, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 11, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 25, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Thyroid hormone receptor beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2592
Polymers31,8341
Non-polymers4251
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.563, 68.563, 129.725
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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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: 31833.533 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 (E. coli) / References: UniProt: P10828
#2: Chemical ChemComp-A1H2J / 6-azanyl-2-[3,5-bis(chloranyl)-4-[(6-oxidanylidene-5-propan-2-yl-1~{H}-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazine-3,5-dione


Mass: 425.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H14Cl2N6O4 / Feature type: SUBJECT OF INVESTIGATION
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: 2.77 Å3/Da / Density % sol: 55.52 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 1.40 M NaAcetate, 0.10 M NaCacodylate pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9999 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 12, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.88→59.38 Å / Num. obs: 7714 / % possible obs: 91.9 % / Redundancy: 12 % / CC1/2: 1 / Rpim(I) all: 0.016 / Rrim(I) all: 0.057 / Net I/σ(I): 22.4
Reflection shellResolution: 2.88→3.01 Å / Mean I/σ(I) obs: 0.8 / Num. unique obs: 386 / CC1/2: 0.451 / Rpim(I) all: 0.871

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Processing

Software
NameVersionClassification
autoPROCdata reduction
XDS(VERSION Jan 26data reduction
autoPROC(Version 1.1.7)data scaling
Aimlessdata scaling
REFMAC5.8.0155refinement
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.88→59.38 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.95 / SU ML: 0.361 / Cross valid method: FREE R-VALUE / ESU R Free: 0.398 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26237 374 4.8 %RANDOM
Rwork0.21573 ---
obs0.2179 7340 91.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-1.14 Å20.57 Å20 Å2
2--1.14 Å2-0 Å2
3----3.69 Å2
Refinement stepCycle: LAST / Resolution: 2.88→59.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1980 0 28 0 2008
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0191896
X-RAY DIFFRACTIONr_bond_other_d0.0030.021730
X-RAY DIFFRACTIONr_angle_refined_deg1.4261.9712585
X-RAY DIFFRACTIONr_angle_other_deg1.2133921
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1565244
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.58723.01473
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.0115273
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.093159
X-RAY DIFFRACTIONr_chiral_restr0.0720.2297
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212176
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02433
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it6.84111.696984
X-RAY DIFFRACTIONr_mcbond_other6.84111.696984
X-RAY DIFFRACTIONr_mcangle_it9.86719.7621225
X-RAY DIFFRACTIONr_mcangle_other9.86319.7691226
X-RAY DIFFRACTIONr_scbond_it7.88412.319912
X-RAY DIFFRACTIONr_scbond_other7.88212.324913
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other11.07520.5871360
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.884→2.959 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.509 8 -
Rwork0.395 129 -
obs--23.06 %
Refinement TLS params.Method: refined / Origin x: 20.021 Å / Origin y: 15.105 Å / Origin z: -19.949 Å
111213212223313233
T0.2769 Å20.0686 Å2-0.2005 Å2-0.0225 Å2-0.0707 Å2--0.4629 Å2
L6.7418 °21.4339 °20.3776 °2-4.6837 °20.2599 °2--5.9568 °2
S-0.4949 Å °-0.1891 Å °0.8213 Å °-0.4877 Å °-0.2274 Å °0.3366 Å °-1.1008 Å °-0.1924 Å °0.7222 Å °

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