5yso

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Crystal structure of Estrogen Related Receptor-3 (ERR-gamma) ligand binding domain with DN200434

Structural highlights

5yso is a 3 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 2.501Å
Ligands:90C
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ERR3_HUMAN Orphan receptor that acts as transcription activator in the absence of bound ligand. Binds specifically to an estrogen response element and activates reporter genes controlled by estrogen response elements (By similarity).[1] [2] [3]

Publication Abstract from PubMed

PURPOSE: New strategies to restore sodium iodide symporter (NIS) expression and function in radioiodine therapy-refractive anaplastic thyroid cancers (ATCs) are urgently required. Recently, we reported the regulatory role of estrogen-related receptor gamma (ERRgamma) in ATC cell NIS function. Herein, we identified DN200434 as a highly potent (functional IC50 = 0.006 muM), selective, and orally available ERRgamma inverse agonist for NIS enhancement in ATC. EXPERIMENTAL DESIGN: We sought to identify better ERRgamma-targeting ligands and explored the crystal structure of ERRgamma in complex with DN200434. After treating ATC cells with DN200434, the change in iodide-handling gene expression as well as radioiodine avidity was examined. ATC tumor-bearing mice were orally administered with DN200434, followed by (124)I-positron emission tomography/computed tomography (PET/CT). For radioiodine therapy, ATC tumor-bearing mice treated with DN200434 were administered (131)I (beta ray-emitting therapeutic radioiodine) and then bioluminescent imaging was performed to monitor the therapeutic effects. Histological analysis was performed to evaluate ERRgamma expression status in normal tissue and ATC tissue, respectively. RESULTS: DN200434-ERRgamma complex crystallographic studies revealed that DN200434 binds to key ERRgamma binding pocket residues through four-way interactions. DN200434 effectively upregulated iodide-handling genes and restored radioiodine avidity in ATC tumor lesions, as confirmed by (124)I-PET/CT. DN200434 enhanced ATC tumor radioiodine therapy susceptibility, markedly inhibiting tumor growth. Histological findings of patients with ATC showed higher ERRgamma expression in tumors than in normal tissue, supporting ERRgamma as a therapeutic target for ATC. CONCLUSIONS: DN200434 shows potential clinical applicability for diagnosis and treatment of ATC or other poorly differentiated thyroid cancers.

A novel orally active inverse agonist of estrogen-related receptor gamma (ERRgamma), DN200434, a booster of NIS in anaplastic thyroid cancer.,Singh TD, Song J, Kim J, Chin J, Ji HD, Lee JE, Lee SB, Yoon H, Yu JH, Kim SK, Yoon GS, Hwang H, Lee HW, Oh JM, Lee SW, Lee J, Choi HS, Na SY, Choi WI, Park YJ, Song YS, Kim YA, Lee IK, Cho SJ, Jeon YH Clin Cancer Res. 2019 Apr 22. pii: 1078-0432.CCR-18-3007. doi:, 10.1158/1078-0432.CCR-18-3007. PMID:31010838[4]

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

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Citations
7 reviews cite this structure
Molecular mechanisms of radioactive iodine refractoriness in differentiated thyroid cancer: Impaired sodium iodide symporter (NIS) expression owing to altered signaling pathway activity and intracellular localization of NIS.
Oh et al. (2021)
6 more
9 other articles
No citations found

See Also

References

  1. ↑ Hentschke M, Susens U, Borgmeyer U. Transcriptional ERRgamma2-mediated activation is regulated by sentrin-specific proteases. Biochem J. 2009 Apr 1;419(1):167-76. doi: 10.1042/BJ20081556. PMID:19067653 doi:10.1042/BJ20081556
  2. ↑ Tremblay AM, Wilson BJ, Yang XJ, Giguere V. Phosphorylation-dependent sumoylation regulates estrogen-related receptor-alpha and -gamma transcriptional activity through a synergy control motif. Mol Endocrinol. 2008 Mar;22(3):570-84. Epub 2007 Dec 6. PMID:18063693 doi:me.2007-0357
  3. ↑ Greschik H, Wurtz JM, Sanglier S, Bourguet W, van Dorsselaer A, Moras D, Renaud JP. Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3. Mol Cell. 2002 Feb;9(2):303-13. PMID:11864604
  4. ↑ Singh TD, Song J, Kim J, Chin J, Ji HD, Lee JE, Lee SB, Yoon H, Yu JH, Kim SK, Yoon GS, Hwang H, Lee HW, Oh JM, Lee SW, Lee J, Choi HS, Na SY, Choi WI, Park YJ, Song YS, Kim YA, Lee IK, Cho SJ, Jeon YH. A novel orally active inverse agonist of estrogen-related receptor gamma (ERRgamma), DN200434, a booster of NIS in anaplastic thyroid cancer. Clin Cancer Res. 2019 Apr 22. pii: 1078-0432.CCR-18-3007. doi:, 10.1158/1078-0432.CCR-18-3007. PMID:31010838 doi:http://dx.doi.org/10.1158/1078-0432.CCR-18-3007

Contents


PDB ID 5yso

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