8RQN

Human thyroid hormone receptor beta ligand binding domain in complex with beta-selective agonist ALG-055009

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.88 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

Discovery and Preclinical Profile of ALG-055009, a Potent and Selective Thyroid Hormone Receptor Beta (THR-beta ) Agonist for the Treatment of MASH.

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.

(2024) J Med Chem 67: 14840-14851

  • DOI: https://doi.org/10.1021/acs.jmedchem.4c01029
  • Primary Citation of Related Structures:  
    8RQN, 8RQO

  • PubMed Abstract: 

    Agonists of thyroid hormone receptor β (THR-β) decreased LDL cholesterol (LDL-C) and triglyceride (TG) levels in human clinical trials for patients with dyslipidemia. The authors present the highly potent and selective compound ALG-055009 ( 14 ) as a potential best in class THR-β agonist. The high metabolic stability and good permeability translated well in vivo to afford a long in vivo half-life pharmacokinetic profile with limited liability for DDI, and it overcomes certain drawbacks seen in recent clinical candidates.

    • Organizational Affiliation: 

    Aligos Belgium BV, Gaston Geenslaan 1, 3001 Leuven, Belgium.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Thyroid hormone receptor beta281Homo sapiensMutation(s): 0 
Gene Names: THRB, ERBA2, NR1A2, THR1
UniProt & NIH Common Fund Data Resources
Find proteins for P10828 (Homo sapiens)
Explore P10828 
Go to UniProtKB:  P10828
PHAROS:  P10828
GTEx:  ENSG00000151090 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP10828
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
A1H2J (Subject of Investigation/LOI)
Query on A1H2J
Download Ideal Coordinates CCD File 
B [auth A]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
C16 H14 Cl2 N6 O4
YZZBNKVFMULQCU-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CAF
Query on CAF
A
L-PEPTIDE LINKINGC5 H12 As N O3 SCYS
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.88 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.563α = 90
b = 68.563β = 90
c = 129.725γ = 120
Software Package:
Software NamePurpose
autoPROCdata reduction
XDSdata reduction
autoPROCdata scaling
Aimlessdata scaling
REFMACrefinement
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History & Funding Information

Deposition Data

Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2024-09-11
    Type: Initial release
  • Version 1.1: 2024-09-25
    Changes: Database references
  • Version 1.2: 2024-11-20
    Changes: Structure summary