8rqo

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

Structural highlights

8rqo is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.74Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

THA_HUMAN Defects in THRA are the cause of congenital hypothyroidism non-goitrous type 6 (CHNG6) [MIM:614450. A disease characterized by growth retardation, developmental retardation, skeletal dysplasia, borderline low thyroxine levels and high triiodothyronine levels. There is differential sensitivity to thyroid hormone action, with retention of hormone responsiveness in the hypothalamic pituitary axis and liver but skeletal, gastrointestinal, and myocardial resistance.[1]

Function

THA_HUMAN Nuclear hormone receptor. High affinity receptor for triiodothyronine.

Publication Abstract from PubMed

Agonists of thyroid hormone receptor beta (THR-beta) 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-beta 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.

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 DC, Luong XG, Stevens SK, Jekle A, Gupta K, Misner DL, Chanda S, Serebryany V, Welch M, Hu H, Lv Z, Williams C, Maskos K, Lammens A, Stoycheva AD, Lin TI, Blatt LM, Beigelman LN, Symons JA, Raboisson P, Deval J J Med Chem. 2024 Sep 2. doi: 10.1021/acs.jmedchem.4c01029. PMID:39221768[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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References

  1. ↑ Bochukova E, Schoenmakers N, Agostini M, Schoenmakers E, Rajanayagam O, Keogh JM, Henning E, Reinemund J, Gevers E, Sarri M, Downes K, Offiah A, Albanese A, Halsall D, Schwabe JW, Bain M, Lindley K, Muntoni F, Vargha-Khadem F, Dattani M, Farooqi IS, Gurnell M, Chatterjee K. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med. 2012 Jan 19;366(3):243-9. doi: 10.1056/NEJMoa1110296. Epub 2011 Dec, 14. PMID:22168587 doi:10.1056/NEJMoa1110296
  2. ↑ Vandyck K, McGowan DC, Luong XG, Stevens SK, Jekle A, Gupta K, Misner DL, Chanda S, Serebryany V, Welch M, Hu H, Lv Z, Williams C, Maskos K, Lammens A, Stoycheva AD, Lin TI, Blatt LM, Beigelman LN, Symons JA, Raboisson P, Deval J. Discovery and Preclinical Profile of ALG-055009, a Potent and Selective Thyroid Hormone Receptor Beta (THR-β) Agonist for the Treatment of MASH. J Med Chem. 2024 Sep 2. PMID:39221768 doi:10.1021/acs.jmedchem.4c01029

Contents


PDB ID 8rqo

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OCA

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