Nature, 20 October, 2022, DOI：https://doi.org/10.1038/s41586-022-05452-z
Recognition of cyclic dinucleotides and folates by human SLC19A1
Qixiang Zhang, Xuyuan Zhang, Yalan Zhu, Panpan Sun, Liwei Zhang, Junxiao Ma, Yong Zhang, Lingan Zeng, Xiaohua Nie, Yina Gao, Zhaolong Li, Songqing Liu, Jizhong Lou, Ang Gao, Liguo Zhang & Pu Gao
Cyclic dinucleotides (CDNs) are ubiquitous signaling molecules in all domains of life. Mammalian cells produce one CDN, 2'3'-cGAMP, by cyclic GMP-AMP synthase upon detecting cytosolic DNA signals. 2'3'-cGAMP, as well as bacterial and synthetic CDN analogs, can act as second messengers to activate stimulator of interferon genes (STING) and elicit broad downstream responses. Extracellular CDNs must traverse the cell membrane to activate STING, a process that is critically dependent on the solute carrier SLC19A1. In addition, SLC19A1 represents the major transporter for folate nutrients and antifolate therapeutics, thereby placing SLC19A1 as a key factor in multiple physiological and pathological processes. How SLC19A1 recognizes and transports CDNs and folate/antifolate is unknown. Here we report cryo-electron microscopy structures of human SLC19A1 (hSLC19A1) in a substrate-free state and in complexes with multiple CDNs from different sources, a predominant natural folate, and a new-generation antifolate drug. Structural and mutagenesis results demonstrate that hSLC19A1 utilizes unique yet divergent mechanisms to recognize CDN- and folate-type substrates. Two CDN molecules bind within the hSLC19A1 cavity as a compact dual-molecule unit, while folate or antifolate binds as a monomer and occupies a distinct pocket of the cavity. Moreover, the structures allow accurate mapping and potential mechanistic interpretation of loss-of-activity and disease-related mutations of hSLC19A1. Our work provides a framework for understanding the mechanism of SLC19 family transporters and serves as a foundation for the development of potential therapeutics.