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- PDB-8gof: Structure of hSLC19A1+PMX -

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Basic information

Entry
Database: PDB / ID: 8gof
TitleStructure of hSLC19A1+PMX
ComponentsReduced folate transporter
KeywordsMEMBRANE PROTEIN / hSLC19A1+PMX complex
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 / xenobiotic transmembrane transport / positive regulation of cGAS/STING signaling pathway / Metabolism of folate and pterines / organic anion transmembrane transporter activity / folic acid binding / antiporter activity / folic acid metabolic process / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / female pregnancy / brush border membrane / basolateral plasma membrane / apical plasma membrane / plasma membrane
Similarity search - Function
Multidrug resistance protein D / Multidrug resistance protein D / Reduced folate transporter SLC19A1 / Reduced folate carrier / Reduced folate carrier / MFS transporter superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-LYA / Reduced folate transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsZhang, Q.X. / Zhang, X.Y. / Zhu, Y.L. / Sun, P.P. / Gao, A. / Zhang, L.G. / Gao, P.
Funding support China, 5items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32130057 China
National Natural Science Foundation of China (NSFC)31922037 China
National Natural Science Foundation of China (NSFC)81921005 China
National Natural Science Foundation of China (NSFC)32171219 China
National Natural Science Foundation of China (NSFC)82001681 China
CitationJournal: Nature / Year: 2022
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
DepositionAug 24, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 5, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 16, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 14, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Jul 3, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Reduced folate transporter
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,9832
Polymers60,5561
Non-polymers4271
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Reduced folate transporter / FOLT / Intestinal folate carrier 1 / IFC-1 / Placental folate transporter / Reduced folate carrier ...FOLT / Intestinal folate carrier 1 / IFC-1 / Placental folate transporter / Reduced folate carrier protein / RFC / hRFC / Reduced folate transporter 1 / RFT-1 / Solute carrier family 19 member 1 / hSLC19A1


Mass: 60556.082 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC19A1, FLOT1, RFC1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P41440
#2: Chemical ChemComp-LYA / 2-{4-[2-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-ETHYL]-BENZOYLAMINO}-PENTANEDIOIC ACID / LY231514


Mass: 427.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21N5O6 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, chemotherapy*YM
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: SLC19A1+PMX / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 189893 / Symmetry type: POINT

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