7zfg | pdb_00007zfg

VDR complex with aromatic D-ring analog

spinqualitylabelsall models 7zfg, resolution 2.62Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7zfg is a 2 chain structure with sequence from Danio rerio and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, IV5 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function VDRA_DANRE Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Regulates transcription of hormone sensitive genes via its association with the WINAC complex, a chromatin-remodeling complex. Plays a central role in calcium homeostasis. Publication Abstract from PubMed The toxic calcemic effects of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (1,25D(3), 1,25-dihydroxycholecalciferol) in the treatment of hyperproliferative diseases demand the development of highly active and noncalcemic vitamin D analogues. We report the development of two highly active and noncalcemic analogues of 1,25D(3) that lack the C-ring and possess an m-phenylene ring that replaces the natural D-ring. The new analogues (3a, 3b) are characterized by an additional six-carbon hydroxylated side chain attached either to the aromatic nucleus or to the triene system. Both compounds were synthesized by the Pd-catalyzed tandem cyclization/cross coupling approach starting from alkyne 6 and diphenol 8. Key steps include a stereoselective Cu-assisted addition of a Grignard reagent to an aromatic alkyne and a Takai olefination of an aromatic aldehyde. The new compounds are noncalcemic and show transcriptional and antiproliferative activities similar to 1,25D(3). Structural analysis revealed that they induce a large conformational rearrangement of the vitamin D receptor around helix 6. Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1alpha,25-Dihydroxyvitamin D(3).,Seoane S, Gogoi P, Zarate-Ruiz A, Peluso-Iltis C, Peters S, Guiberteau T, Maestro MA, Perez-Fernandez R, Rochel N, Mourino A J Med Chem. 2022 Oct 13;65(19):13112-13124. doi: 10.1021/acs.jmedchem.2c00900. , Epub 2022 Sep 27. PMID:36166643 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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