5B41

Crystal structure of VDR-LBD complexed with 2-methylidene-19-nor-1a,25-dihydroxyvitamin D3

Summary for 5B41

• Entry DOI: 10.2210/pdb5b41/pdb
• Descriptor: Vitamin D3 receptor, Mediator of RNA polymerase II transcription subunit 1, (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-6-hydroxy-6-methylheptan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2- methylenecyclohexane-1,3-diol, ... (4 entities in total)
• Functional Keywords: transcription, vitamin d3, vdr, vdre, rxr, co-factors
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 2
• Total formula weight: 32582.57

Authors

Anami, Y.,Itoh, T.,Yamamoto, K. (deposition date: 2016-03-23, release date: 2016-12-07, Last modification date: 2023-11-08)

Primary citation

Anami, Y.,Shimizu, N.,Ekimoto, T.,Egawa, D.,Itoh, T.,Ikeguchi, M.,Yamamoto, K.
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
J.Med.Chem., 59:7888-7900, 2016

PubMed Abstract: Vitamin D receptor (VDR) controls the expression of numerous genes through the conformational change caused by binding 1α,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.

PubMed: 27535484
DOI: 10.1021/acs.jmedchem.6b00682

Experimental method

X-RAY DIFFRACTION (1.89 Å)