Chen Jinli, Duan Yanwei, Zhou Yuanyuan, Yang Qing
State Key Laboratory for Biology of Plant Diseases and Insect Pests, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China; Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China; School of Bioengineering, Dalian University of Technology, Dalian 116024, China.
Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
Cell. 2025 Feb 20;188(4):944-957.e19. doi: 10.1016/j.cell.2024.11.033. Epub 2024 Dec 24.
ATP-binding cassette (ABC) transporter subfamily H is only identified in arthropods and zebrafish. It transports lipids and is related to insecticide resistance. However, the precise mechanisms of its functions remain elusive. Here, we report cryoelectron microscopy (cryo-EM) structures of an ABCH from Tribolium castaneum, a worldwide pest of stored grains, in complex with an HEK293 cell-ceramide lipid, a fluorescent-labeled ceramide, a carbamate insecticide, and a maltose detergent inhibitor. We revealed a narrow, long, and arched substrate-binding tunnel in the transmembrane domains of the transporter dimer with two arginine-gated cytoplasmic entries for the binding and transport of lipids or insecticides. A pair of glutamines above the tunnel acts as a gate for directing substrate to be extruded via a vent-like hydrophilic exit to the extracellular side of the membrane upon ATP binding. Our structures and biochemical data provide mechanistic understanding of lipid transport, insecticide detoxification, and the inhibition of transporter activity by branched maltose detergents.
ATP结合盒（ABC）转运蛋白H亚家族仅在节肢动物和斑马鱼中被发现。它负责运输脂质，且与杀虫剂抗性有关。然而，其功能的确切机制仍不清楚。在此，我们报告了来自全球储粮害虫赤拟谷盗的一种ABCH与HEK293细胞神经酰胺脂质、荧光标记神经酰胺、氨基甲酸酯类杀虫剂和麦芽糖去污剂抑制剂形成复合物的冷冻电镜结构。我们揭示了转运蛋白二聚体跨膜结构域中一个狭窄、细长且呈拱形的底物结合通道，有两个精氨酸门控的胞质入口用于脂质或杀虫剂的结合和运输。通道上方的一对谷氨酰胺作为一个门，用于在ATP结合时引导底物通过类似通风口的亲水性出口挤出到膜的细胞外侧。我们的结构和生化数据为脂质运输、杀虫剂解毒以及支链麦芽糖去污剂对转运蛋白活性的抑制提供了机制上的理解。
