Wang Ke, Chen Huiwen, Cheng Lili, Zhao Jun, Huang Bo, Wu Di, He Xin, Zhou Yumeng, Yuan Yaxuan, Zhou Feng, Jiang Juquan, Chen Ligong, Jiang Daohua
Department of Microbiology and Biotechnology, College of Life Sciences, Northeast Agricultural University, Harbin, China.
Beijing National Laboratory for Condensed Matter Physics and Institute of Physics, Chinese Academy of Sciences, Beijing, China.
Nat Commun. 2025 May 1;16(1):4078. doi: 10.1038/s41467-025-59255-7.
Riboflavin (vitamin B2) is the precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which act as key cofactors of many enzymes, thus has essential roles in cell growth and functions. Animals cannot synthesize riboflavin in situ, the intake, distribution and metabolism of which are mediated by three riboflavin transporters (RFVT1-3). Many mutations in RFVTs cause severe consequences. How RFVTs recognize and transport riboflavin remains largely unknown. Here we describe the cryo-electron microscopy structures of human RFVT2 and RFVT3 in complex with riboflavin in outward-occluded and inward-open states, respectively. Riboflavin is recognized by a conserved binding pocket in the central cavity of RFVTs, whereas two acidic residues in RFVT3 determine its pH-dependent activity. By combining the structural, computational and functional analyses, this study demonstrates the structural basis of riboflavin recognition and provides a structural framework for the mechanistic comprehension of riboflavin recognition, transport, and pathology in human RFVTs.
核黄素（维生素B2）是黄素单核苷酸（FMN）和黄素腺嘌呤二核苷酸（FAD）的前体，它们作为许多酶的关键辅助因子，因此在细胞生长和功能中起着至关重要的作用。动物无法在体内原位合成核黄素，其摄取、分布和代谢由三种核黄素转运蛋白（RFVT1 - 3）介导。RFVTs中的许多突变会导致严重后果。RFVTs如何识别和转运核黄素在很大程度上仍然未知。在这里，我们分别描述了处于向外封闭和向内开放状态的与核黄素结合的人RFVT2和RFVT3的冷冻电子显微镜结构。核黄素由RFVTs中央腔中的一个保守结合口袋识别，而RFVT3中的两个酸性残基决定了其pH依赖性活性。通过结合结构、计算和功能分析，本研究揭示了核黄素识别的结构基础，并为理解人类RFVTs中核黄素识别、转运和病理学的机制提供了一个结构框架。
