期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 17, 页码 7888-7900出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00682
关键词
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资金
- Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- Japan Agency for Medical Research and Development (AMED)
- MEXT [26460155, hp150269, hp160223]
- Grants-in-Aid for Scientific Research [26460155] Funding Source: KAKEN
Vitamin D receptor (VDR) controls the expression of numerous genes through the conformational change caused by binding 1 alpha,25-dihydroxyvitamin D-3. Helix 12 in the ligand-lpinding 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, arid loop 1112 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 deseribe the mechanism of agonism/antagonism of VDR-LBD,
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