[English] 日本語
Yorodumi
- EMDB-33387: Structure of hSLC19A1+3'3'-CDA -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-33387
TitleStructure of hSLC19A1+3'3'-CDA
Map data
Sample
  • Complex: SLC19A1+3'3'-CDA
    • Protein or peptide: Reduced folate transporter
  • Ligand: (2R,3R,3aS,5R,7aR,9R,10R,10aS,12R,14aR)-2,9-bis(6-amino-9H-purin-9-yl)octahydro-2H,7H-difuro[3,2-d:3',2'-j][1,3,7,9,2,8 ]tetraoxadiphosphacyclododecine-3,5,10,12-tetrol 5,12-dioxide
Function / homology
Function and homology information


folic acid transmembrane transporter activity / folate:monoatomic anion antiporter activity / methotrexate transport / folate transmembrane transport / methotrexate transmembrane transporter activity / folic acid transport / folate import across plasma membrane / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / organic anion transport ...folic acid transmembrane transporter activity / folate:monoatomic anion antiporter activity / methotrexate transport / folate transmembrane transport / methotrexate transmembrane transporter activity / folic acid transport / folate import across plasma membrane / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / organic anion transport / 2',3'-cyclic GMP-AMP binding / xenobiotic transmembrane transport / organic anion transmembrane transporter activity / Metabolism of folate and pterines / antiporter activity / folic acid binding / 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
Reduced folate transporter SLC19A1 / Reduced folate carrier / Reduced folate carrier / MFS transporter superfamily
Similarity search - Domain/homology
Reduced folate transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsZhang QX / Zhang XY / Zhu YL / Sun PP / Gao A / Zhang LG / Gao P
Funding support China, 5 items
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
DepositionMay 6, 2022-
Header (metadata) releaseOct 5, 2022-
Map releaseOct 5, 2022-
UpdateDec 14, 2022-
Current statusDec 14, 2022Processing site: PDBj / Status: Released

-
Structure visualization

Supplemental images

emd_33387.png

Downloads & links

-
Map

FileDownload / File: emd_33387.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1 Å
Density
Contour LevelBy AUTHOR: 0.025
Minimum - Maximum-0.1272093 - 0.21453983
Average (Standard dev.)1.9519879e-05 (±0.0043105655)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 320.0 Å
α=β=γ: 90.0 °

-
Supplemental data

-
Half map: #1

Fileemd_33387_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: #2

Fileemd_33387_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
Entire : SLC19A1+3'3'-CDA

EntireName: SLC19A1+3'3'-CDA
Components
  • Complex: SLC19A1+3'3'-CDA
    • Protein or peptide: Reduced folate transporter
  • Ligand: (2R,3R,3aS,5R,7aR,9R,10R,10aS,12R,14aR)-2,9-bis(6-amino-9H-purin-9-yl)octahydro-2H,7H-difuro[3,2-d:3',2'-j][1,3,7,9,2,8 ]tetraoxadiphosphacyclododecine-3,5,10,12-tetrol 5,12-dioxide

-
Supramolecule #1: SLC19A1+3'3'-CDA

SupramoleculeName: SLC19A1+3'3'-CDA / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

-
Macromolecule #1: Reduced folate transporter

MacromoleculeName: Reduced folate transporter / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 60.556082 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: 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

-
Macromolecule #2: (2R,3R,3aS,5R,7aR,9R,10R,10aS,12R,14aR)-2,9-bis(6-amino-9H-purin-...

MacromoleculeName: (2R,3R,3aS,5R,7aR,9R,10R,10aS,12R,14aR)-2,9-bis(6-amino-9H-purin-9-yl)octahydro-2H,7H-difuro[3,2-d:3',2'-j][1,3,7,9,2,8 ]tetraoxadiphosphacyclododecine-3,5,10,12-tetrol 5,12-dioxide
type: ligand / ID: 2 / Number of copies: 2 / Formula: 2BA
Molecular weightTheoretical: 658.412 Da

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

-
Electron microscopy

MicroscopeFEI TALOS ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

-
Image processing

Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 242868

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more