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- EMDB-61690: outward-open hSLC19A1 -

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Basic information

Entry
Database: EMDB / ID: EMD-61690
Titleoutward-open hSLC19A1
Map data
Sample
  • Complex: outward-open hSLC19A1
    • Protein or peptide: Soluble cytochrome b562,Reduced folate transporter,fusion protein
Keywordsoutward-open hSLC19A1 / MEMBRANE PROTEIN
Function / homology
Function and homology information


folate:monoatomic anion antiporter activity / methotrexate transport / folic acid transmembrane transporter activity / methotrexate transmembrane transporter activity / folic acid transport / folate transmembrane transport / folate import across plasma membrane / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / 2',3'-cyclic GMP-AMP binding ...folate:monoatomic anion antiporter activity / methotrexate transport / folic acid transmembrane transporter activity / methotrexate transmembrane transporter activity / folic acid transport / folate transmembrane transport / folate import across plasma membrane / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / 2',3'-cyclic GMP-AMP binding / organic anion transport / Metabolism of folate and pterines / xenobiotic transmembrane transport / organic anion transmembrane transporter activity / positive regulation of cGAS/STING signaling pathway / folic acid binding / antiporter activity / folic acid metabolic process / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / female pregnancy / electron transport chain / brush border membrane / response to toxic substance / basolateral plasma membrane / electron transfer activity / periplasmic space / apical plasma membrane / iron ion binding / response to xenobiotic stimulus / heme binding / plasma membrane
Similarity search - Function
Reduced folate transporter SLC19A1 / Reduced folate carrier / Reduced folate carrier / Cytochrome b562 / Cytochrome b562 / MFS transporter superfamily / Cytochrome c/b562
Similarity search - Domain/homology
Soluble cytochrome b562 / Reduced folate transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.94 Å
AuthorsZhang QX / Liu KX / Gao P
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2025
Title: Molecular basis of SLC19A1-mediated folate and cyclic dinucleotide transport.
Authors: Qixiang Zhang / Xuyuan Zhang / Kexin Liu / Yalan Zhu / Xiaohua Nie / Junxiao Ma / Panpan Sun / Zhaolong Li / Yina Gao / Songqing Liu / Ang Gao / Liguo Zhang / Pu Gao /
Abstract: The solute carrier protein SLC19A1 is crucial for transporting folate nutrients, antifolate chemotherapeutics, and more recently cyclic dinucleotides (CDNs) immune transmitters, influencing various ...The solute carrier protein SLC19A1 is crucial for transporting folate nutrients, antifolate chemotherapeutics, and more recently cyclic dinucleotides (CDNs) immune transmitters, influencing various physiological and pathological processes. While the inward-open state of human SLC19A1 (hSLC19A1) has been previously described, key aspects regarding its conformational dynamics, substrate selectivity, and precise mechanisms underlying CDNs transport remain elusive. Using an antibody-facilitated conformation screening strategy, we present cryo-electron microscopy structures of hSLC19A1 in its outward-open state with and without bound substrates, revealing detailed mechanisms of substrate recognition and conformational changes during transport. We identify both general and specific features for folate/antifolate recognition, including an SLC19A1-specific pocket for accommodating γ-carboxylate-modified antifolates. Intriguingly, CDNs bind as monomers within the canonical pocket of outward-open hSLC19A1, contrasting with dimeric binding in inward-open structures. Together with functional assays, these findings provide a framework for developing antifolate drugs and CDN-targeted therapies, advancing our understanding of SLC19A1's physiological and therapeutic functions.
History
DepositionSep 25, 2024-
Header (metadata) releaseFeb 26, 2025-
Map releaseFeb 26, 2025-
UpdateApr 23, 2025-
Current statusApr 23, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

Downloads & links

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Map

FileDownload / File: emd_61690.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1 Å/pix.
x 256 pix.
= 256. Å
1 Å/pix.
x 256 pix.
= 256. Å
1 Å/pix.
x 256 pix.
= 256. Å

Surface

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1 Å
Density
Contour LevelBy AUTHOR: 0.85
Minimum - Maximum-6.044876 - 7.9793015
Average (Standard dev.)-0.00069503876 (±0.11762297)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 256.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_61690_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Half map: #1

Fileemd_61690_half_map_2.map
Projections & Slices
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Sample components

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Entire : outward-open hSLC19A1

EntireName: outward-open hSLC19A1
Components
  • Complex: outward-open hSLC19A1
    • Protein or peptide: Soluble cytochrome b562,Reduced folate transporter,fusion protein

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Supramolecule #1: outward-open hSLC19A1

SupramoleculeName: outward-open hSLC19A1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Soluble cytochrome b562,Reduced folate transporter,fusion protein

MacromoleculeName: Soluble cytochrome b562,Reduced folate transporter,fusion protein
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 77.480914 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MADLEDNWET LNDNLKVIEK ADNAAQVKDA LTKMRAAALD AQKATPPKLE DKSPDSPEMK DFRHGFDILV GQIDDALKLA NEGKVKEAQ AAAEQLKTTR NAYIQKYLSW RHLVCYLCFY GFMAQIRPGE SFITPYLLGP DKQFTREQVT NEITPVLSYS Y LAVLVPVF ...String:
MADLEDNWET LNDNLKVIEK ADNAAQVKDA LTKMRAAALD AQKATPPKLE DKSPDSPEMK DFRHGFDILV GQIDDALKLA NEGKVKEAQ AAAEQLKTTR NAYIQKYLSW RHLVCYLCFY GFMAQIRPGE SFITPYLLGP DKQFTREQVT NEITPVLSYS Y LAVLVPVF LLTDYLRYTP VLLLQGLSFV SVWLLLLLGH SVAHMQLMEL FYSVTMAARI AYSSYIFSLV RPARYQRVAG YS RAAVLLG VFTSSVLGQL LVTVGRVSFS TLNYISLAFL TFSVVLALFL KRPKRSLFFN RDDRGRCETS ASELERMNPG PGG KLGHAL RVACGDSVLA RMLRELGDSL RRPQLRLWSL WWVFNSAGYY LVVYYVHILW NEVDPTTNSA RVYNFAADAA STLL GAITS FAAGFVKIRW ARWSKLLIAG VTATQAGLVF LLAHTRHPSS IWLCYAAFVL FRGSYQFLVP IATFQIASSL SKELC ALVF GVNTFFATIV KTIITFIVSD VRGLGLPVRK QFQLYSVYFL ILSIIYFLGA MLDGLRHAEE EKRKAEEEKR KGSGSQ VQL QESGGGLVQP GGSLRLSCAA SGRTISRYAM SWFRQAPGKE REFVAVARRS GDGAFYADSV QGRFTVSRDD AKNTVYL QM NSLKPEDTAV YYCAIDSDTF YSGSYDYWGQ GTQVTVSSHH HHHHHHHH

UniProtKB: Soluble cytochrome b562, Reduced folate transporter

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.0 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.94 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 345903
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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