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

被引：23

作者：

Anami, Yasuaki ^{[1
]}

Shimizu, Nobutaka ^{[2
]}

Eldmoto, Toni ^{[3
]}

Egawa, Daichi ^{[1
]}

Itoh, Toshimasa ^{[1
]}

Ikeguch, Mitsunori ^{[3
]}

Yamamoto, Keiko ^{[1
]}

机构：

[1] Showa Pharmaceut Univ, Lab Drug Design & Med Chem, 3-3165 Higashi Tamagawagakuen, Machida, Tokyo 1948543, Japan

[2] High Energy Accelerator Res Org KEK, Inst Materials Struct Sci, Photon Factory, 1-1 Oho, Tsukuba, Ibaraki 3050801, Japan

[3] Yokohama City Univ, Grad Sch Med Life Sci, Tsurumi Ku, 1-7-29 Suehiro cho, Yokohama, Kanagawa 2300045, Japan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 17期

关键词：

GENERAL FORCE-FIELD; NUCLEAR RECEPTOR; CRYSTAL-STRUCTURE; D ANALOGS; PARTIAL AGONISM; CHARMM; RXR; RECOGNITION; MODULATION; AUTOMATION;

D O I：

10.1021/acs.jmedchem.6b00682

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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,

引用

页码：7888 / 7900

页数：13

共 76 条

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