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- PDB-8rqo: Human thyroid hormone receptor alpha ligand binding domain in com... -

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Basic information

Entry
Database: PDB / ID: 8rqo
TitleHuman thyroid hormone receptor alpha ligand binding domain in complex with beta-selective agonist ALG-055009
ComponentsIsoform Alpha-1 of Thyroid hormone receptor alpha
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


regulation of myeloid cell apoptotic process / negative regulation of DNA-templated transcription initiation / negative regulation of RNA polymerase II transcription preinitiation complex assembly / female courtship behavior / regulation of lipid catabolic process / thyroid hormone binding / thyroid hormone receptor signaling pathway / positive regulation of thyroid hormone receptor signaling pathway / regulation of thyroid hormone receptor signaling pathway / positive regulation of female receptivity ...regulation of myeloid cell apoptotic process / negative regulation of DNA-templated transcription initiation / negative regulation of RNA polymerase II transcription preinitiation complex assembly / female courtship behavior / regulation of lipid catabolic process / thyroid hormone binding / thyroid hormone receptor signaling pathway / positive regulation of thyroid hormone receptor signaling pathway / regulation of thyroid hormone receptor signaling pathway / positive regulation of female receptivity / cartilage condensation / regulation of heart contraction / type I pneumocyte differentiation / thyroid gland development / general transcription initiation factor binding / retinoic acid receptor signaling pathway / hormone-mediated signaling pathway / ossification / response to cold / TBP-class protein binding / erythrocyte differentiation / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / chromatin DNA binding / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / nuclear receptor activity / positive regulation of cold-induced thermogenesis / transcription by RNA polymerase II / cell differentiation / DNA-binding transcription factor activity, RNA polymerase II-specific / learning or memory / transcription cis-regulatory region binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein domain specific binding / negative regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / chromatin / protein-containing complex binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
Thyroid hormone receptor / : / 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 ...Thyroid hormone receptor / : / 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 alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.74 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: Isoform Alpha-1 of Thyroid hormone receptor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7723
Polymers32,2511
Non-polymers5212
Water25214
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area260 Å2
ΔGint-16 kcal/mol
Surface area13010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.199, 110.199, 134.579
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522

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Components

#1: Protein Isoform Alpha-1 of Thyroid hormone receptor alpha / Nuclear receptor subfamily 1 group A member 1 / V-erbA-related protein 7 / EAR-7 / c-erbA-1 / c-erbA-alpha


Mass: 32251.098 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: THRA, EAR7, ERBA1, NR1A1, THRA1, THRA2 / Production host: Escherichia coli (E. coli) / References: UniProt: P10827
#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
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / 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: 3.66 Å3/Da / Density % sol: 66.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1 M ADA pH 6.5, 1 M Ammoniumsulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9999 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 11, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.74→95.45 Å / Num. obs: 12868 / % possible obs: 97.2 % / Redundancy: 4.2 % / CC1/2: 1 / Rmerge(I) obs: 0.044 / Rrim(I) all: 0.051 / Net I/σ(I): 19.7
Reflection shellResolution: 2.74→2.99 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.45 / Mean I/σ(I) obs: 3.33 / Num. unique obs: 2920 / CC1/2: 0.859 / Rrim(I) all: 0.515 / % possible all: 98.5

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0155refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.74→95.45 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.945 / SU B: 22.213 / SU ML: 0.208 / Cross valid method: FREE R-VALUE / ESU R: 0.395 / ESU R Free: 0.264 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22784 750 5.8 %RANDOM
Rwork0.19348 ---
obs0.19534 12118 97.17 %-
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
1-0.44 Å20.22 Å20 Å2
2--0.44 Å2-0 Å2
3----1.43 Å2
Refinement stepCycle: LAST / Resolution: 2.74→95.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2052 0 33 14 2099
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0192079
X-RAY DIFFRACTIONr_bond_other_d0.0030.021979
X-RAY DIFFRACTIONr_angle_refined_deg1.541.9852817
X-RAY DIFFRACTIONr_angle_other_deg1.2534544
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9765255
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.27223.44490
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.33315358
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.1441513
X-RAY DIFFRACTIONr_chiral_restr0.0830.2317
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212323
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02458
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_it6.0527.7221026
X-RAY DIFFRACTIONr_mcbond_other6.0337.7191025
X-RAY DIFFRACTIONr_mcangle_it8.97613.0461279
X-RAY DIFFRACTIONr_mcangle_other8.98113.0531280
X-RAY DIFFRACTIONr_scbond_it7.3848.3691053
X-RAY DIFFRACTIONr_scbond_other7.218.3451050
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other10.29213.7621533
X-RAY DIFFRACTIONr_long_range_B_refined12.4569.6782211
X-RAY DIFFRACTIONr_long_range_B_other12.44769.6832212
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.74→2.811 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.391 61 -
Rwork0.331 886 -
obs--98.65 %
Refinement TLS params.Method: refined / Origin x: 43.507 Å / Origin y: 12.271 Å / Origin z: 26.501 Å
111213212223313233
T0.0455 Å2-0.0219 Å2-0.0348 Å2-0.0259 Å20.0435 Å2--0.0895 Å2
L2.4126 °21.0387 °2-1.4047 °2-5.2404 °2-2.5056 °2--3.9369 °2
S-0.1533 Å °-0.0025 Å °-0.1681 Å °-0.1804 Å °0.3 Å °0.3686 Å °0.2218 Å °-0.1726 Å °-0.1468 Å °

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