5b41
From Proteopedia
Crystal structure of VDR-LBD complexed with 2-methylidene-19-nor-1a,25-dihydroxyvitamin D3
Structural highlights
FunctionVDR_RAT 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. Recruited to promoters via its interaction with the WINAC complex subunit BAZ1B/WSTF, which mediates the interaction with acetylated histones, an essential step for VDR-promoter association. Plays a central role in calcium homeostasis.[1] Publication Abstract from PubMedVitamin D receptor (VDR) controls the expression of numerous genes through the conformational change caused by binding 1alpha,25-dihydroxyvitamin D3. Helix 12 in the ligand-binding domain (LBD) is key to regulating VDR activation. The structures of apo VDR-LBD and the VDR-LBD/antagonist complex are unclear. Here, we reveal their unprecedented structures in solution using a hybrid method combining small-angle X-ray scattering and molecular dynamics simulations. In apo rat VDR-LBD, helix 12 is partially unraveled, and it is positioned around the canonical active position and fluctuates. Helix 11 greatly bends toward the outside at Q396, creating a kink. In the rat VDR-LBD/antagonist complex, helix 12 does not generate the activation function 2 surface, and loop 11-12 is remarkably flexible compared to that in the apo rat VDR-LBD. On the basis of these structural insights, we propose a "folding-door model" to describe the mechanism of agonism/antagonism of VDR-LBD. Apo- and Antagonist-Binding Structures of Vitamin D Receptor Ligand-Binding Domain Revealed by Hybrid Approach Combining Small-Angle X-ray Scattering and Molecular Dynamics.,Anami Y, Shimizu N, Ekimoto T, Egawa D, Itoh T, Ikeguchi M, Yamamoto K J Med Chem. 2016 Sep 8;59(17):7888-900. doi: 10.1021/acs.jmedchem.6b00682. Epub, 2016 Aug 26. PMID:27535484[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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