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- EMDB-41081: Cryo-EM structure of human Anion Exchanger 1 bound to Dipyridamole -
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Open data
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Basic information
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Title | Cryo-EM structure of human Anion Exchanger 1 bound to Dipyridamole | ||||||||||||
![]() | structure of human Anion Exchanger 1 bound to Dipyridamole | ||||||||||||
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![]() | Transmembrane / TRANSPORT PROTEIN | ||||||||||||
Function / homology | ![]() pH elevation / Defective SLC4A1 causes hereditary spherocytosis type 4 (HSP4), distal renal tubular acidosis (dRTA) and dRTA with hemolytic anemia (dRTA-HA) / negative regulation of urine volume / Bicarbonate transporters / intracellular monoatomic ion homeostasis / ankyrin-1 complex / plasma membrane phospholipid scrambling / monoatomic anion transmembrane transporter activity / chloride:bicarbonate antiporter activity / solute:inorganic anion antiporter activity ...pH elevation / Defective SLC4A1 causes hereditary spherocytosis type 4 (HSP4), distal renal tubular acidosis (dRTA) and dRTA with hemolytic anemia (dRTA-HA) / negative regulation of urine volume / Bicarbonate transporters / intracellular monoatomic ion homeostasis / ankyrin-1 complex / plasma membrane phospholipid scrambling / monoatomic anion transmembrane transporter activity / chloride:bicarbonate antiporter activity / solute:inorganic anion antiporter activity / bicarbonate transport / bicarbonate transmembrane transporter activity / monoatomic anion transport / chloride transport / chloride transmembrane transporter activity / ankyrin binding / negative regulation of glycolytic process through fructose-6-phosphate / hemoglobin binding / cortical cytoskeleton / erythrocyte development / protein-membrane adaptor activity / chloride transmembrane transport / protein localization to plasma membrane / regulation of intracellular pH / Erythrocytes take up oxygen and release carbon dioxide / Erythrocytes take up carbon dioxide and release oxygen / cytoplasmic side of plasma membrane / transmembrane transport / Z disc / blood coagulation / basolateral plasma membrane / blood microparticle / protein homodimerization activity / extracellular exosome / membrane / plasma membrane Similarity search - Function | ||||||||||||
Biological species | ![]() | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.13 Å | ||||||||||||
![]() | Capper MJ / Zilberg G / Mathiharan YK / Yang S / Stone AC / Wacker D | ||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Substrate binding and inhibition of the anion exchanger 1 transporter. Authors: Michael J Capper / Shifan Yang / Alexander C Stone / Sezen Vatansever / Gregory Zilberg / Yamuna Kalyani Mathiharan / Raul Habib / Keino Hutchinson / Yihan Zhao / Avner Schlessinger / Mihaly ...Authors: Michael J Capper / Shifan Yang / Alexander C Stone / Sezen Vatansever / Gregory Zilberg / Yamuna Kalyani Mathiharan / Raul Habib / Keino Hutchinson / Yihan Zhao / Avner Schlessinger / Mihaly Mezei / Roman Osman / Bin Zhang / Daniel Wacker / ![]() Abstract: Anion exchanger 1 (AE1), a member of the solute carrier (SLC) family, is the primary bicarbonate transporter in erythrocytes, regulating pH levels and CO transport between lungs and tissues. Previous ...Anion exchanger 1 (AE1), a member of the solute carrier (SLC) family, is the primary bicarbonate transporter in erythrocytes, regulating pH levels and CO transport between lungs and tissues. Previous studies characterized its role in erythrocyte structure and provided insight into transport regulation. However, key questions remain regarding substrate binding and transport, mechanisms of drug inhibition and modulation by membrane components. Here we present seven cryo-EM structures in apo, bicarbonate-bound and inhibitor-bound states. These, combined with uptake and computational studies, reveal important molecular features of substrate recognition and transport, and illuminate sterol binding sites, to elucidate distinct inhibitory mechanisms of research chemicals and prescription drugs. We further probe the substrate binding site via structure-based ligand screening, identifying an AE1 inhibitor. Together, our findings provide insight into mechanisms of solute carrier transport and inhibition. | ||||||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 72 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 21.9 KB 21.9 KB | Display Display | ![]() |
Images | ![]() | 113.4 KB | ||
Filedesc metadata | ![]() | 7 KB | ||
Others | ![]() ![]() ![]() | 136.5 MB 134 MB 134 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8t6uMC ![]() 7ty4C ![]() 7ty6C ![]() 7ty7C ![]() 7ty8C ![]() 7tyaC ![]() 8t6vC 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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Map
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Annotation | structure of human Anion Exchanger 1 bound to Dipyridamole | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.076 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: Additional Map
File | emd_41081_additional_1.map | ||||||||||||
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Annotation | Additional Map | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half Map 1
File | emd_41081_half_map_1.map | ||||||||||||
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Annotation | Half Map 1 | ||||||||||||
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Density Histograms |
-Half map: Half Map 2
File | emd_41081_half_map_2.map | ||||||||||||
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Annotation | Half Map 2 | ||||||||||||
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Density Histograms |
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Sample components
-Entire : Dimeric anion exchanger 1 (SLC4A1)
Entire | Name: Dimeric anion exchanger 1 (SLC4A1) |
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Components |
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-Supramolecule #1: Dimeric anion exchanger 1 (SLC4A1)
Supramolecule | Name: Dimeric anion exchanger 1 (SLC4A1) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 203 KDa |
-Macromolecule #1: Band 3 anion transport protein
Macromolecule | Name: Band 3 anion transport protein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 58.254105 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: DDPLQQTGQL FGGLVRDIRR RYPYYLSDIT DAFSPQVLAA VIFIYFAALS PAITFGGLLG EKTRNQMGVS ELLISTAVQG ILFALLGAQ PLLVVGFSGP LLVFEEAFFS FCETNGLEYI VGRVWIGFWL ILLVVLVVAF EGSFLVRFIS RYTQEIFSFL I SLIFIYET ...String: DDPLQQTGQL FGGLVRDIRR RYPYYLSDIT DAFSPQVLAA VIFIYFAALS PAITFGGLLG EKTRNQMGVS ELLISTAVQG ILFALLGAQ PLLVVGFSGP LLVFEEAFFS FCETNGLEYI VGRVWIGFWL ILLVVLVVAF EGSFLVRFIS RYTQEIFSFL I SLIFIYET FSKLIKIFQD HPLQKTYNYN VLMVPKPQGP LPNTALLSLV LMAGTFFFAM MLRKFKNSSY FPGKLRRVIG DF GVPISIL IMVLVDFFIQ DTYTQKLSVP DGFKVSNSSA RGWVIHPLGL RSEFPIWMMF ASALPALLVF ILIFLESQIT TLI VSKPER KMVKGSGFHL DLLLVVGMGG VAALFGMPWL SATTVRSVTH ANALTVMGKA STPGAAAQIQ EVKEQRISGL LVAV LVGLS ILMEPILSRI PLAVLFGIFL YMGVTSLSGI QLFDRILLLF KPPKYHPDVP YVKRVKTWRM HLFTGIQIIC LAVLW VVKS TPASLALPFV LILTVPLRRV LLPLIFRNVE LQCLDADDA UniProtKB: Band 3 anion transport protein |
-Macromolecule #3: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 8 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ![]() ChemComp-CLR: |
-Macromolecule #4: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
Macromolecule | Name: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 4 / Number of copies: 2 / Formula: PC1 |
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Molecular weight | Theoretical: 790.145 Da |
Chemical component information | ![]() ChemComp-PC1: |
-Macromolecule #5: 2-[[2-[bis(2-hydroxyethyl)amino]-4,8-di(piperidin-1-yl)pyrimido[5...
Macromolecule | Name: 2-[[2-[bis(2-hydroxyethyl)amino]-4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidin-6-yl]-(2-hydroxyethyl)amino]ethanol type: ligand / ID: 5 / Number of copies: 2 / Formula: H9F |
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Molecular weight | Theoretical: 504.626 Da |
Chemical component information | ![]() ChemComp-H9F: |
-Macromolecule #6: water
Macromolecule | Name: water / type: ligand / ID: 6 / Number of copies: 36 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ![]() ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 4.8 mg/mL | ||||||||||||
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Buffer | pH: 7.5 Component:
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Vitrification | Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 285 K / Instrument: LEICA EM GP Details: Blot force 3 for 3-5 seconds was used and subsequent grids were screened for ice thickness prior to data collection. | ||||||||||||
Details | The sample was monodisperse following gel filtration and immediately concentrated for grid preparation |
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Electron microscopy
Microscope | TFS KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 4570 / Average electron dose: 51.69 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 64000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |