EMD-33386

Single-particle
3.4 Å
EMD-33386 Deposition: 06/05/2022
Map released: 05/10/2022
Last modified: 03/07/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-33386

Structure of Apo-hSLC19A1

EMD-33386

Single-particle
3.4 Å
EMD-33386 Deposition: 06/05/2022
Map released: 05/10/2022
Last modified: 03/07/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: SLC19A1
Fitted models: 7xpz (Avg. Q-score: 0.508)

Deposition Authors: Zhang QX, Zhang XY, Zhu YL, Sun PP, Gao A , Zhang LG, Gao P
Recognition of cyclic dinucleotides and folates by human SLC19A1.
Zhang Q , Zhang X , Zhu Y, Sun P, Zhang L , Ma J, Zhang Y, Zeng L, Nie X, Gao Y, Li Z, Liu S, Lou J , Gao A , Zhang L , Gao P
(2022) Nature , 612 , 170 - 176
PUBMED: 36265513
DOI: doi:10.1038/s41586-022-05452-z
ISSN: 1476-4687
ASTM: NATUAS
Abstract:
Cyclic dinucleotides (CDNs) are ubiquitous signalling molecules in all domains of life1,2. Mammalian cells produce one CDN, 2'3'-cGAMP, through cyclic GMP-AMP synthase after detecting cytosolic DNA signals3-7. 2'3'-cGAMP, as well as bacterial and synthetic CDN analogues, can act as second messengers to activate stimulator of interferon genes (STING) and elicit broad downstream responses8-21. Extracellular CDNs must traverse the cell membrane to activate STING, a process that is dependent on the solute carrier SLC19A122,23. Moreover, SLC19A1 represents the major transporter for folate nutrients and antifolate therapeutics24,25, thereby placing SLC19A1 as a key factor in multiple physiological and pathological processes. How SLC19A1 recognizes and transports CDNs, folate and antifolate is unclear. 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. The structural and mutagenesis results demonstrate that hSLC19A1 uses 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, whereas folate and antifolate bind as a monomer and occupy a distinct pocket of the cavity. Moreover, the structures enable accurate mapping and potential mechanistic interpretation of hSLC19A1 with loss-of-activity and disease-related mutations. Our research provides a framework for understanding the mechanism of SLC19-family transporters and is a foundation for the development of potential therapeutics.