Magnetic properties of (Bi1-xLax)(Fe,Co)O-3 films fabricated by a pulsed DC reactive sputtering and demonstration of magnetization reversal by electric field

(Bi1-xLax)(Fe,Co)O-3 multiferroic magnetic film were fabricated using pulsed DC (direct current) sputtering technique and demonstrated magnetization reversal by applied electric field. The fabricated (Bi0.41La0.59)(Fe0.75Co0.25)O-3 films exhibited hysteresis curves of both ferromagnetic and ferroelectric behavior. The saturated magnetization (M-s) of the multiferroic film was about 70 emu/cm(3). The squareness (S) (=remanent magnetization (M-r)/M-s) and coercivity (H-c) of perpendicular to film plane are 0.64 and 4.2 kOe which are larger compared with films in parallel to film plane of 0.5 and 2.5 kOe. The electric and magnetic domain structures of the (Bi0.41La0.59)(Fe0.75Co0.25)O-3 film analyzed by electric force microscopy (EFM) and magnetic force microscopy (MFM) were clearly induced with submicron scale by applying a local electric field. This magnetization reversal indicates the future realization of high performance magnetic device with low power consumption

Natural ligand-nonmimetic inhibitors of the lipid-transfer protein CERT

Lipid transfer proteins mediate inter-organelle transport of membrane lipids at organelle contact sites in cells, playing fundamental roles in the lipidome and membrane biogenesis in eukaryotes. We previously developed a ceramide-mimetic compound as a potent inhibitor of the ceramide transport protein CERT. Here we develop CERT inhibitors with structures unrelated to ceramide. To this aim, we identify a seed compound with no ceramide-like structure but with the capability of forming a hydrogen-bonding network in the ceramide-binding START domain, by virtual screening of ~3 × 106 compounds. We also establish a surface plasmon resonance-based system to directly determine the affinity of compounds for the START domain. Then, we subject the seed compound to a series of in silico docking simulations, efficient chemical synthesis, affinity analysis, protein-ligand co-crystallography, and various in vivo assays. This strategy allows us to obtain ceramide-unrelated compounds that potently inhibited the function of CERT in human cultured cells

Characterization of Covalent Bond Formation between PPARγ and Oxo-Fatty Acids

Covalent modification of proteins is important for normal cellular regulation. Here, we report on the covalent modification of peroxisome proliferator-activated receptor γ (PPARγ), an important drug target, by oxo-fatty acids. In this study, ESI mass spectroscopy showed that the reactivities of oxo-fatty acids with PPARγ are different from one another and that these behaviors are related to the structure of the fatty acids. X-ray crystallography showed that three oxo-fatty acids all bound to the same residue of PPARγ (Cys285), but displayed different hydrogen bonding modes. Moreover, fatty acids formed covalent bonds with both PPARγ moieties in the homodimer, one in an active conformation and the other in an alternative conformation. These two conformations may explain why covalently bound fatty acids show partial rather than full agonist activity

Helix12-Stabilization Antagonist of Vitamin D Receptor

To develop strong vitamin D receptor (VDR) antagonists and reveal their antagonistic mechanism, we designed and synthesized vitamin D analogues with bulky side chains based on the “active antagonist” concept in which antagonist prevents helix 12 (H12) folding. Of the synthesized analogues, compounds <b>3a</b> and <b>3b</b> showed strong antagonistic activity. Dynamic hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) and static X-ray crystal structure analyses indicated that compound <b>3a</b> stabilizes H11–H12 but displaces H6–H7 so that <b>3a</b> is a novel rather than “active” or “passive” type of antagonist. We classified <b>3a</b> as a third type of antagonist and called it “H11–H12 stabilization antagonist”. HDX-MS analysis indicated that antagonist <b>3b</b> is an “active” antagonist. To date there are no reports relating to nuclear receptor antagonist that strongly stabilizes H12. In this study, we found first VDR antagonist that stabilizes H12 and we showed that antagonistic mechanism is diverse depending on each antagonist structure. Additionally, HDX-MS was proven to be very useful for investigations of protein structure alterations resulting from ligand binding

Involvement of a cluster of basic amino acids in phosphoryla-tion-dependent functional repression of the ceramide transport protein CERT

The uncropped images of western blots, the unprocessed images of immunofluorescence, and raw data obtained in this study are deposited in this Figshare site

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

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

MOESM1 of Clinical effect of a dentifrice containing three kinds of bactericidal ingredients on periodontal disease: a pilot study in patients undergoing supportive periodontal therapy

Additional file 1: Table S1. Subjective evaluation by participants: Questionnaire items