title: 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.
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.
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University , 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Anami
authors.affiliation: Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK) , 1-1 Oho, Tsukuba, Ibaraki 305-0801, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: Graduate School of Medical Life Science, Yokohama City University , 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Ekimoto
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University , 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Egawa
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University , 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Graduate School of Medical Life Science, Yokohama City University , 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Ikeguchi
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University , 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001059:Apoproteins / Q000737:chemistry*; D001665:Binding Sites; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000737:chemistry; D018360:Crystallography, X-Ray; D008024:Ligands; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D000072417:Protein Domains; D051381:Rats; D018167:Receptors, Calcitriol / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D053838:Scattering, Small Angle; D012996:Solutions; D014965:X-Rays
chemical_list: D001059:Apoproteins; D008024:Ligands; D018167:Receptors, Calcitriol; D012996:Solutions; D002762:Cholecalciferol