5gs4

Crystal structure of estrogen receptor alpha in complex with a stabilized peptide antagonist

spinqualitylabelsall models 5gs4, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5gs4 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EST, PO4 NonStd Res: DNP, IAS, NH2 Gene: ESR1, ESR, NR3A1 (HUMAN) 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 Direct inhibition of the protein-protein interaction of ERalpha and its endogenous coactivators with a cell permeable stabilized peptide may offer a novel, promising strategy for combating ERalpha positive breast cancers. Here, we report the co-crystal structure of a helical peptide stabilized by a N-terminal unnatural cross-linked aspartic acid (TD) in complex with the ERalpha ligand binding domain (LBD). We designed a series of peptides and peptide 6 that showed direct and high-affinity binding to ERalpha with selective antiproliferative activity in ERalpha positive breast cancer cells. The co-crystal structure of the TD-stabilized peptide 6 in complex with ERalpha LBD further demonstrates that it forms an alpha helical conformation and directly binds at the coactivator binding site of ERalpha. Further studies showed that peptide 6W could potently inhibit cellular ERalpha's transcriptional activity. This approach demonstrates the potential of TD stabilized peptides to modulate various intracellular protein-protein interactions involved in a range of disorders. Structural Basis of Inhibition of ERalpha-Coactivator Interaction by High-Affinity N-Terminus Isoaspartic Acid Tethered Helical Peptides.,Xie M, Zhao H, Liu Q, Zhu Y, Yin F, Liang Y, Jiang Y, Wang D, Hu K, Qin X, Wang Z, Wu Y, Xu N, Ye X, Wang T, Li Z J Med Chem. 2017 Nov 9;60(21):8731-8740. doi: 10.1021/acs.jmedchem.7b00732. Epub , 2017 Oct 31. PMID:29045135 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Estrogen receptor

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