Serine hydroxymethyltransferase (SHMT) produces 5,10-methylenetetrahydrofolate (CH2-THF) from tetrahydrofolate with serine to glycine conversion. SHMT is a potential drug target in parasites, viruses and cancer. (+)-SHIN-1 was developed as a human SHMT inhibitor for cancer therapy. However, the potential of SHMT as an antibacterial target is unknown. Here, we show that (+)-SHIN-1 bacteriostatically inhibits the growth of Enterococcus faecium at a 50% effective concentration of 10–11 M and synergistically enhances the antibacterial activities of several nucleoside analogues. Our results, including crystal structure analysis, indicate that (+)-SHIN-1 binds tightly to E. faecium SHMT (efmSHMT). Two variable loops in SHMT are crucial for inhibitor binding, and serine binding to efmSHMT enhances the affinity of (+)-SHIN-1 by stabilising the loop structure of efmSHMT. The findings highlight the potency of SHMT as an antibacterial target and the possibility of developing SHMT inhibitors for treating bacterial, viral and parasitic infections and cancer.
IntroductionIn recent decades, researchers have attempted to construct and investigate new molecule-based magnetic materials; this has resulted in numerous new findings such as organic ferromagnets, [1] single-molecule magnets, [2] singlechain magnets, [3] magnetically controlled conductivities, [4] and chiral magnets.[5] However, although magnetic molecules can exhibit many of the aforementioned interesting properties, the application and investigation of these materials has been quite limited because of their weak intermolecular exchange interactions. For example, most of the molecule-based magnetic materials exhibit only weak intermolecular interactions |2J|/k B Ͻ 20 K; [6] k B is the Boltzmann constant, and J is defined in the following Hamiltonian [Equation (1)].(1)As the influence of intermolecular exchange interactions is far weaker than the influence of thermal fluctuations at room temperature, the interesting magnetic behavior can be observed only in the very low temperature region in many cases; therefore, the application of molecule-based magnetic [a]
Glycans-protein interaction is essential for a variety of biological functions and diseases. However, the inherent flexibility of the glycan molecules makes conventional X-ray or NMR structural analysis quite difficult. Here, we employ molecular dynamics (MD) simulations to reveal the glycanprotein complex structures in atomic details. To this end, we revised the current CHARMM force field for carbohydrates by refitting the parameters so as to increase the accuracy in the potential for the α1-6 glycosidic bond. Replica-exchange MD simulations, with extensive sampling of N-glycan structures in solution, show that our revised force filed parameters better reproduce the experimental NMR data and more accurately represent glycan rotameric conformations.
Protein motions occur over a wide range of time scales, but not all are important for protein functions, which time scales are generally longer. Thus, it would be reasonable to consider that slower motions of proteins are more relevant to their functions. To identify such slow protein dynamics from simulation results, we have proposed the time-structure based independent component analysis (tICA). In the present study, we selected lysine-, arginine-, ornithine-binding protein (LAO) as a target protein, and performed one-microsecond molecular dynamics simulation in explicit water. By applying the tICA to the simulation results, several motions in the LAO were identified as slow modes, and were confirmed with additional analyses to be actually occurred. 1P050 トリプリオンタンパク質に対する抗体 G2 の複数の抗原を特 異的に認識する性質の特徴付け Characterization of multispecific monoclonal antibody G2 directed against chicken prion protein
Elucidation of the folding process of proteins is indispensable for understanding how proteins acquire a unique conformation. To this goal, we recently developed two-dimensional fluorescence lifetime correlation spectroscopy (2D FLCS). In the Biophysical society meeting last year, we reported a 2D FLCS study on the conformational transition dynamics of B domain of protein A (BdpA). The obtained results suggested that the conformational dynamics of BdpA occur within 10 microseconds. In this study, 2D FLCS was performed for two mutants of BdpA in which FRET pairs are attached on different positions. The results strongly suggested that the folding process of BdpA does not fit the simple two-state model. In the presentation, we discuss the folding mechanism of BdpA. 1P056たった 10 残基から成るタンパク質の立体構造安定性に及ぼ The small protein with only 10 residues, CLN025, folds into the β-hairpin structure. We show that the enthalpy increase arising from the break of hydrogen bonds with water molecules is compensated by the enthalpy decrease due to intramolecular hydrogen bonding. The water-entropy (WE) gain arising from close packing of the backbone and side chains including those with the four large aromatic residues is powerful enough to surpass the conformational-entropy (CE) loss. In its design template (GPM12) with only two aromatic residues, however, the WE gain yields to the CE loss though there is no enthalpy change, and the unfolded state is stabilized. The above elucidation is made possible by decomposing our free-energy function into physically insightful constituents. 1P057 カルシトニンアミロイド凝集機構の解明と抑制法の考案 Analysis of amyloid formation and inhibition mechanisms of human calcitoninHiroko Tanaka, Hironari Kamikubo, Yoichi Yamazaki, Mikio Kataoka (Grad. Sch. Mat. Sci., NAIST)Human calcitonin (hCT) is a peptide hormone used as a medicine. It easily forms amyloid fibrils to reduce the efficiency. Salmon calcitonin (sCT) is known to inhibit amyloid formation of hCT. We revealed that the chimera peptides derived from sCT and hCT suppresses the amyloid formation. In order to develop an inhibitor of hCT amyloid formation, we aimed to clarify the inhibition mechanism. We measured the amyloid fibrillation process by thioflavin T fluorescence. The fluorescence intensity decreases with increasing the molar ratio of the chimera CT. The amyloid formation was completely suppressed by the equivalent amount of chimeric CT, indicating that hetero-dimer comprising hCT and the chimera CT forms at the initial process and inhibits the further fibrillation. 1P058 分子動力学シミュレーションを用いたリガンド結合による PR-Set7 の構造変化の研究 Molecular dynamics simulations for structure changes of PR- Set7 by ligand bindingTakako Sakano, Hideaki Fujitani (RCAST, UTokyo) X-ray crystal structure of a target protein is used to find new active molecules, Virtual Screening, or their docking pose prediction. However, some X-ray crystal structures are not suitable for such purposes, because some proteins significantly change their structure by allosteric effect of ligand binding. We obtained apo stru...
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