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Yorodumi- EMDB-12935: Structure of thermostable human MFSD2A in complex with thermostab... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-12935 | |||||||||
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Title | Structure of thermostable human MFSD2A in complex with thermostable human Sync2 | |||||||||
Map data | Thermostable human MFSD2A transporter in complex with thermostable human SYNC2 | |||||||||
Sample |
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Function / homology | Function and homology information lysophosphatidylcholine flippase activity / regulation of phosphatidylethanolamine metabolic process / regulation of phosphatidylserine metabolic process / oleate transmembrane transporter activity / regulation of phosphatidylcholine metabolic process / regulation of neuron projection arborization / retina morphogenesis in camera-type eye / fatty acid transmembrane transporter activity / photoreceptor cell morphogenesis / lysophospholipid translocation ...lysophosphatidylcholine flippase activity / regulation of phosphatidylethanolamine metabolic process / regulation of phosphatidylserine metabolic process / oleate transmembrane transporter activity / regulation of phosphatidylcholine metabolic process / regulation of neuron projection arborization / retina morphogenesis in camera-type eye / fatty acid transmembrane transporter activity / photoreceptor cell morphogenesis / lysophospholipid translocation / lysophospholipid:sodium symporter activity / lysophospholipid transport / syncytium formation by plasma membrane fusion / syncytium formation / photoreceptor cell outer segment organization / lipid transport across blood-brain barrier / very-low-density lipoprotein particle assembly / negative regulation of fatty acid beta-oxidation / regulation of dendrite development / retinal pigment epithelium development / phospholipid transporter activity / positive regulation of triglyceride biosynthetic process / phosphatidylcholine biosynthetic process / : / establishment of blood-brain barrier / myoblast fusion / transcytosis / motor behavior / long-chain fatty acid transmembrane transporter activity / maintenance of blood-brain barrier / Synthesis of PC / plasma membrane => GO:0005886 / carbohydrate transport / transport across blood-brain barrier / regulation of multicellular organism growth / fatty acid transport / long-chain fatty acid transport / energy homeostasis / cellular response to starvation / hippocampus development / brain development / cognition / positive regulation of cell growth / membrane => GO:0016020 / endoplasmic reticulum membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.6 Å | |||||||||
Authors | Martinez-Molledo M / Reyes N | |||||||||
Funding support | European Union, 1 items
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Citation | Journal: Nat Struct Mol Biol / Year: 2022 Title: Structural insights into the lysophospholipid brain uptake mechanism and its inhibition by syncytin-2. Authors: Maria Martinez-Molledo / Emmanuel Nji / Nicolas Reyes / Abstract: Brain development and function require uptake of essential omega-3 fatty acids in the form of lysophosphatidylcholine via major-facilitator superfamily transporter MFSD2A, a potential pharmaceutical ...Brain development and function require uptake of essential omega-3 fatty acids in the form of lysophosphatidylcholine via major-facilitator superfamily transporter MFSD2A, a potential pharmaceutical target to modulate blood-brain barrier (BBB) permeability. MFSD2A is also the receptor of endogenous retroviral envelope syncytin-2 (SYNC2) in human placenta, where it mediates cell-cell fusion and formation of the maternal-fetal interface. Here, we report a cryo-electron microscopy structure of the human MFSD2A-SYNC2 complex that reveals a large hydrophobic cavity in the transporter C-terminal domain to occlude long aliphatic chains. The transporter architecture suggests an alternating-access transport mechanism for lipid substrates in mammalian MFS transporters. SYNC2 establishes an extensive binding interface with MFSD2A, and a SYNC2-soluble fragment acts as a long-sought-after inhibitor of MFSD2A transport. Our work uncovers molecular mechanisms important to brain and placenta development and function, and SYNC2-mediated inhibition of MFSD2A transport suggests strategies to aid delivery of therapeutic macromolecules across the BBB. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_12935.map.gz | 266.6 MB | EMDB map data format | |
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Header (meta data) | emd-12935-v30.xml emd-12935.xml | 16.7 KB 16.7 KB | Display Display | EMDB header |
Images | emd_12935.png | 34.9 KB | ||
Others | emd_12935_additional_1.map.gz | 266.7 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-12935 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-12935 | HTTPS FTP |
-Related structure data
Related structure data | 7oixMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_12935.map.gz / Format: CCP4 / Size: 282.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Thermostable human MFSD2A transporter in complex with thermostable human SYNC2 | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.814 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: Additional map for thermostable human MFSD2A transporter in...
File | emd_12935_additional_1.map | ||||||||||||
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Annotation | Additional map for thermostable human MFSD2A transporter in complex with thermostable human SYNC2 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Thermostable human MFSD2A in complex with thermostable human Sync...
Entire | Name: Thermostable human MFSD2A in complex with thermostable human Syncytin-2 |
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Components |
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-Supramolecule #1: Thermostable human MFSD2A in complex with thermostable human Sync...
Supramolecule | Name: Thermostable human MFSD2A in complex with thermostable human Syncytin-2 type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) / Recombinant cell: HEK-293F |
-Macromolecule #1: Syncytin-2
Macromolecule | Name: Syncytin-2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 59.613219 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MGLLLLVLIL TPSLAAYRHP DFPLLEKAQQ LLQSTGSPYS TNCWLCTSSS TETPGTAYPA SPREWTSIEA ELHISYRWDP NLKGLMRPA NSLLSTVKQD FPDIRQKPPI FGPIFTNINL MGIAPICVTA KRKNGTNVGT LPSTVCNVTF TVDPNQQTYQ T YTHNQFRH ...String: MGLLLLVLIL TPSLAAYRHP DFPLLEKAQQ LLQSTGSPYS TNCWLCTSSS TETPGTAYPA SPREWTSIEA ELHISYRWDP NLKGLMRPA NSLLSTVKQD FPDIRQKPPI FGPIFTNINL MGIAPICVTA KRKNGTNVGT LPSTVCNVTF TVDPNQQTYQ T YTHNQFRH QPRFPKPPNI TFPQGTLLDK STRFCQGRPS SCSTRNFWFR PADYNQCLQI SNLSSTAEWV LLDQTRNSLF WE NKTKGAN QSQTPCVQVL AGMTIATSYL GISAVSEFFG TSLTPLFHFH ISTCLKTQGA FYICGQSIHQ CLPSNWTGTC TIG YVTPDI FIAPGNLSLP IPIYGNSPLP RVRRAIHFIP LLAGLGILAG TGTGIAGITK ASLTYSQLSK EIANNIDTMA KALT TMQEQ IDSLAAVVLQ NRRGLDMLTA AQGGICLALD EKCCFWVNQS GKVQDNIRQL LNQASSLRER ATQGWLNWEG TWKWF SWVL PFIGPLVSLL LLLLFGPCLL NLITQFVSSR LQAIKLQTNL SAGRHPRNIQ ESPF |
-Macromolecule #2: Isoform 2 of Sodium-dependent lysophosphatidylcholine symporter 1
Macromolecule | Name: Isoform 2 of Sodium-dependent lysophosphatidylcholine symporter 1 type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 58.540805 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MAKGEGAESG SAAGLLPTSI LQSTERPAQV KKEPKKKKQQ LSICNKLCYA VGGAPYQVTG CALGFFLQIY LLDVAQVGPF SASIILFVG RAWDAITDPL VGFCISKSSW TRLGRLMPWI IFSTPLAVIA YFLIWFVPDF PHGQTYWYLL FYCLFETLVT C FHVPYSAL ...String: MAKGEGAESG SAAGLLPTSI LQSTERPAQV KKEPKKKKQQ LSICNKLCYA VGGAPYQVTG CALGFFLQIY LLDVAQVGPF SASIILFVG RAWDAITDPL VGFCISKSSW TRLGRLMPWI IFSTPLAVIA YFLIWFVPDF PHGQTYWYLL FYCLFETLVT C FHVPYSAL TMFISTEQSE RDSATAYRMT VEVLGTVLGT AIQGQIVGQA DTPCFQDLNS STVASQSANH THGTTSHRET QN AYLLAAG VIASIYVICA VILTLGVREQ REPYEAQQSE PMSFFRGLRL VMSHGPYIKL IAGFLFTSLA FMLVEGNFAL FCT YTLGFR NEFQNLLLAI MLSATLTIPI WQWFLTRFGK KTAVYVGISS AVPFLILVAL MESNLIVTYV VAVAAGISVA AAFL LPWSM LPDVIDDFHL KQPHSHGTEP IFFSFYVFFT KFASGVSLGI STLSLDFAGY QTRGCSQPER VKFTLKMLVT MAPIV LILL GLLLFKLYPI DEERRRQNKK ALQALRDEAS SSGCSETDST ELASIL |
-Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 5 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 1.2 mg/mL | ||||||||||||
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Buffer | pH: 7.4 Component:
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Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Pretreatment - Type: GLOW DISCHARGE / Details: 2 mA | ||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 47.1 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.5 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
+Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: AB INITIO MODEL |
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Output model | PDB-7oix: |