6chw

Estrogen Receptor Alpha Y537S covalently bound to antagonist H3B-5942.

spinqualitylabelsall models 6chw, resolution 1.89Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6chw 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 1.89Å Ligands: DMS, EDO, F3D Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ESR1_HUMAN Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Isoform 3 can bind to ERE and inhibit isoform 1. Publication Abstract from PubMed Mutations in estrogen receptor alpha (ERa) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Since a significant proportion of therapy-resistant breast cancer metastases continue to be dependent on ERa signaling, there remains a critical need to develop the next generation of ERa antagonists that can overcome aberrant ERa activity. Through our drug discovery efforts, we identified H3B-5942 which covalently inactivates both wild-type and mutant ERa by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ERa antagonist referred to as Selective Estrogen Receptor Covalent Antagonists (SERCAs). In vitro comparisons of H3B-5942 with standard of care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERa(WT) and ERa(MUT) cell lines. In vivo, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERa(WT) and ERa(Y537S) breast cancer that was superior to fulvestrant. Lastly, H3B-5942 potency can be further improved in combination with CDK4/6 or mTOR inhibitors in both ERa(WT) and ERa(MUT) cell lines and/or tumor models. In summary, H3B-5942 belongs to a class of orally available ERa covalent antagonists with an improved profile over SoCs. Discovery of Selective Estrogen Receptor Covalent Antagonists (SERCAs) for the treatment of ERa(WT) and ERa(MUT) breast cancer.,Puyang X, Furman C, Zheng GZ, Wu ZJ, Banka D, Aithal B K, Agoulnik S, Bolduc DM, Buonamici S, Caleb B, Das S, Eckley S, Fekkes P, Hao MH, Hart A, Houtman R, Irwin S, Joshi JJ, Karr C, Kim A, Kumar N, Kumar P, Kuznetsov G, Lai WG, Larsen N, MacKenzie C, Martin LA, Melchers D, Moriarty A, Nguyen TV, Norris J, O'Shea M, Pancholi S, Prajapati S, Rajagopalan S, Reynolds DJ, Rimkunas V, Rioux N, Ribas R, Siu A, Sivakumar S, Subramanian V, Thomas M, Vaillancourt FH, Wang J, Wardell S, Wick MJ, Yao S, Yu L, Warmuth M, Smith PG, Zhu P, Korpal M Cancer Discov. 2018 Jul 10. pii: 2159-8290.CD-17-1229. doi:, 10.1158/2159-8290.CD-17-1229. PMID:29991605 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Estrogen receptor 3D structures

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