L'Institut de Chimie et Biologie des Membranes et des Nano-Objets (CBMN), Unité Mixte de Recherche (UMR) 5248, Centre National de la Recherche (CNRS), University of Bordeaux, Pessac 33600, France.
J Chem Inf Model. 2020 Mar 23;60(3):1368-1375. doi: 10.1021/acs.jcim.9b01020. Epub 2020 Feb 11.
Because of its specific physicochemical properties (fluorescence, photosensitizing, and redox reactions), vitamin B2, also called riboflavin (RF), has been generating a lot of interest in the fields of nanotechnology and bioengineering in the last decade. RF, by targeting its riboflavin transporters (RFVTs) overexpressed in some cancers, is particularly used to functionalize nanovectors for anticancer drug delivery. From a physiopathological point of view, an RF deficiency has been implicated in various pathologies, including mendelian diseases. RF deficiency is mainly due to natural variants of its RFVTs that make them inactive and therefore prevent RF transport. The lack of structural data about RFVT is a major drawback for a better understanding of the role of the mutations in the molecular mechanism of these transporters. In this context, this work was aimed at investigating the 3D structure of RFVT3 and its interactions with RF. For this purpose, we used an in silico procedure including protein threading, docking, and molecular dynamics. Our results propose that the natural variant W17R, known to be responsible for the Brown-Vialetto-Van Laere syndrome, prevents the recognition of RF by RFVT3 and thus blocks its transport. This in silico procedure could be used for elucidating the impact of pathogenic mutations of other proteins. Moreover, the identification of RF binding sites will be useful for the design of RF-functionalized nanovectors.
由于其特殊的物理化学性质（荧光、光敏和氧化还原反应），维生素 B2，也称为核黄素（RF），在过去十年中在纳米技术和生物工程领域引起了广泛关注。RF 通过靶向其在某些癌症中过度表达的核黄素转运蛋白（RFVTs），特别用于为抗癌药物输送功能化纳米载体。从生理病理学的角度来看，RF 缺乏与各种病理学有关，包括孟德尔疾病。RF 缺乏主要是由于其 RFVTs 的天然变异使其失活，从而阻止 RF 转运。缺乏关于 RFVT 的结构数据是对这些转运蛋白的分子机制中突变作用更好理解的主要障碍。在这种情况下，这项工作旨在研究 RFVT3 的 3D 结构及其与 RF 的相互作用。为此，我们使用了包括蛋白质穿线、对接和分子动力学在内的计算程序。我们的结果表明，已知导致 Brown-Vialetto-Van Laere 综合征的天然变异 W17R 阻止了 RFVT3 对 RF 的识别，从而阻止了其转运。这种计算程序可用于阐明其他蛋白质的致病性突变的影响。此外，鉴定 RF 结合位点将有助于设计 RF 功能化纳米载体。
