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Open data
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Basic information
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Title | Structure of Apo-hSLC19A1 | ||||||||||||||||||
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![]() | SLC19A1 / MEMBRANE PROTEIN | ||||||||||||||||||
Function / homology | ![]() folic acid transmembrane transporter activity / folate:monoatomic anion antiporter activity / methotrexate transport / methotrexate transmembrane transporter activity / folic acid transport / folate transmembrane transport / folate import across plasma membrane / positive regulation of cGAS/STING signaling pathway / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane ...folic acid transmembrane transporter activity / folate:monoatomic anion antiporter activity / methotrexate transport / methotrexate transmembrane transporter activity / folic acid transport / folate transmembrane transport / folate import across plasma membrane / positive regulation of cGAS/STING signaling pathway / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / organic anion transport / 2',3'-cyclic GMP-AMP binding / organic anion transmembrane transporter activity / xenobiotic transmembrane transport / Metabolism of folate and pterines / antiporter activity / folic acid binding / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / folic acid metabolic process / female pregnancy / brush border membrane / basolateral plasma membrane / apical plasma membrane / plasma membrane Similarity search - Function | ||||||||||||||||||
Biological species | ![]() | ||||||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.4 Å | ||||||||||||||||||
![]() | Zhang QX / Zhang XY / Zhu YL / Sun PP / Gao A / Zhang LG / Gao P | ||||||||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Recognition of cyclic dinucleotides and folates by human SLC19A1. Authors: 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 / ![]() Abstract: Cyclic dinucleotides (CDNs) are ubiquitous signalling molecules in all domains of life. Mammalian cells produce one CDN, 2'3'-cGAMP, through cyclic GMP-AMP synthase after detecting cytosolic DNA ...Cyclic dinucleotides (CDNs) are ubiquitous signalling molecules in all domains of life. Mammalian cells produce one CDN, 2'3'-cGAMP, through cyclic GMP-AMP synthase after detecting cytosolic DNA signals. 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 responses. Extracellular CDNs must traverse the cell membrane to activate STING, a process that is dependent on the solute carrier SLC19A1. Moreover, 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, 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. | ||||||||||||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 117 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 14.9 KB 14.9 KB | Display Display | ![]() |
Images | ![]() | 47.6 KB | ||
Filedesc metadata | ![]() | 5.3 KB | ||
Others | ![]() ![]() | 98.4 MB 98.4 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 804.2 KB | Display | ![]() |
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Full document | ![]() | 803.8 KB | Display | |
Data in XML | ![]() | 12.1 KB | Display | |
Data in CIF | ![]() | 14.6 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7xpzMC ![]() 7xq0C ![]() 7xq1C ![]() 7xq2C ![]() 8goeC ![]() 8gofC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 1 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #1
File | emd_33386_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_33386_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
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Sample components
-Entire : SLC19A1
Entire | Name: SLC19A1 |
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Components |
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-Supramolecule #1: SLC19A1
Supramolecule | Name: SLC19A1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Reduced folate transporter
Macromolecule | Name: Reduced folate transporter / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 60.556082 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MGSMVPSSPA VEKQVPVEPG PDPELRSWRH LVCYLCFYGF MAQIRPGESF ITPYLLGPDK NFTREQVTNE ITPVLSYSYL AVLVPVFLL TDYLRYTPVL LLQGLSFVSV WLLLLLGHSV AHMQLMELFY SVTMAARIAY SSYIFSLVRP ARYQRVAGYS R AAVLLGVF ...String: MGSMVPSSPA VEKQVPVEPG PDPELRSWRH LVCYLCFYGF MAQIRPGESF ITPYLLGPDK NFTREQVTNE ITPVLSYSYL AVLVPVFLL TDYLRYTPVL LLQGLSFVSV WLLLLLGHSV AHMQLMELFY SVTMAARIAY SSYIFSLVRP ARYQRVAGYS R AAVLLGVF TSSVLGQLLV TVGRVSFSTL NYISLAFLTF SVVLALFLKR PKRSLFFNRD DRGRCETSAS ELERMNPGPG GK LGHALRV ACGDSVLARM LRELGDSLRR PQLRLWSLWW VFNSAGYYLV VYYVHILWNE VDPTTNSARV YNGAADAAST LLG AITSFA AGFVKIRWAR WSKLLIAGVT ATQAGLVFLL AHTRHPSSIW LCYAAFVLFR GSYQFLVPIA TFQIASSLSK ELCA LVFGV NTFFATIVKT IITFIVSDVR GLGLPVRKQF QLYSVYFLIL SIIYFLGAML DGLRHCQRGH HPRQPPAQGL RSAAE EKAA QALSVQDKGL GGLQPAQSPP LSPEDKLGSE NLYLEVLFQG PFQGGSGGSG HHHHHHHHHH UniProtKB: Reduced folate transporter |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TALOS ARCTICA |
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Image recording | Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | ![]() Model: Talos Arctica / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: OTHER |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 361966 |
Initial angle assignment | Type: PROJECTION MATCHING |
Final angle assignment | Type: PROJECTION MATCHING |