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. 2016 Sep 8;59(17):7888-900. doi: 10.1021/acs.jmedchem.6b00682.
Yasuaki Anami  1 ,  Nobutaka Shimizu  2 ,  Toru Ekimoto  3 ,  Daichi Egawa  1 ,  Toshimasa Itoh  1 ,  Mitsunori Ikeguchi  3 ,  Keiko Yamamoto  1
Affiliations
  • 1. Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University , 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
  • 2. Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK) , 1-1 Oho, Tsukuba, Ibaraki 305-0801, Japan.
  • 3. Graduate School of Medical Life Science, Yokohama City University , 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
PMID: 27535484 DOI: 10.1021/acs.jmedchem.6b00682
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.

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