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Open data
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Basic information
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Title | Structure of human SGLT2-MAP17 complex with Dapagliflozin | |||||||||
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![]() | Ion transport / Sodium transport / Sugar transport / Symport / Transport / TRANSPORT PROTEIN | |||||||||
Function / homology | ![]() low-affinity glucose:sodium symporter activity / Defective SLC5A2 causes renal glucosuria (GLYS1) / alpha-glucoside transport / alpha-glucoside transmembrane transporter activity / glucose:sodium symporter activity / hexose transmembrane transport / D-glucose transmembrane transporter activity / Cellular hexose transport / renal glucose absorption / glucose import across plasma membrane ...low-affinity glucose:sodium symporter activity / Defective SLC5A2 causes renal glucosuria (GLYS1) / alpha-glucoside transport / alpha-glucoside transmembrane transporter activity / glucose:sodium symporter activity / hexose transmembrane transport / D-glucose transmembrane transporter activity / Cellular hexose transport / renal glucose absorption / glucose import across plasma membrane / sodium ion import across plasma membrane / sodium ion transport / carbohydrate metabolic process / apical plasma membrane / extracellular exosome / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.8 Å | |||||||||
![]() | Hiraizumi M / Kishida H / Miyaguchi I / Nureki O | |||||||||
Funding support | 1 items
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![]() | ![]() Title: Transport and inhibition mechanism of the human SGLT2-MAP17 glucose transporter. Authors: Masahiro Hiraizumi / Tomoya Akashi / Kouta Murasaki / Hiroyuki Kishida / Taichi Kumanomidou / Nao Torimoto / Osamu Nureki / Ikuko Miyaguchi / ![]() Abstract: Sodium-glucose cotransporter 2 (SGLT2) is imporant in glucose reabsorption. SGLT2 inhibitors suppress renal glucose reabsorption, therefore reducing blood glucose levels in patients with type 2 ...Sodium-glucose cotransporter 2 (SGLT2) is imporant in glucose reabsorption. SGLT2 inhibitors suppress renal glucose reabsorption, therefore reducing blood glucose levels in patients with type 2 diabetes. We and others have developed several SGLT2 inhibitors starting from phlorizin, a natural product. Using cryo-electron microscopy, we present the structures of human (h)SGLT2-MAP17 complexed with five natural or synthetic inhibitors. The four synthetic inhibitors (including canagliflozin) bind the transporter in the outward conformations, while phlorizin binds it in the inward conformation. The phlorizin-hSGLT2 interaction exhibits biphasic kinetics, suggesting that phlorizin alternately binds to the extracellular and intracellular sides. The Na-bound outward-facing and unbound inward-open structures of hSGLT2-MAP17 suggest that the MAP17-associated bundle domain functions as a scaffold, with the hash domain rotating around the Na-binding site. Thus, Na binding stabilizes the outward-facing conformation, and its release promotes state transition to inward-open conformation, exhibiting a role of Na in symport mechanism. These results provide structural evidence for the Na-coupled alternating-access mechanism proposed for the transporter family. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 2 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 16.3 KB 16.3 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 6.4 KB | Display | ![]() |
Images | ![]() | 168.7 KB | ||
Filedesc metadata | ![]() | 6.2 KB | ||
Others | ![]() ![]() | 6.1 MB 6.1 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8hezMC ![]() 8hb0C ![]() 8hdhC ![]() 8hg7C ![]() 8hinC 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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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 1.10667 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_34705_half_map_1.map | ||||||||||||
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Density Histograms |
-Half map: #1
File | emd_34705_half_map_2.map | ||||||||||||
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Density Histograms |
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Sample components
-Entire : Binary complex of Sodium/glucose cotransporter 2 with PDZK1-inter...
Entire | Name: Binary complex of Sodium/glucose cotransporter 2 with PDZK1-interacting protein 1. |
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Components |
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-Supramolecule #1: Binary complex of Sodium/glucose cotransporter 2 with PDZK1-inter...
Supramolecule | Name: Binary complex of Sodium/glucose cotransporter 2 with PDZK1-interacting protein 1. type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 Details: Electrogenic Na+-coupled sugar simporter that actively transports D-glucose at the plasma membrane, with a Na+ to sugar coupling ratio of 1:1. Transporter activity is driven by a ...Details: Electrogenic Na+-coupled sugar simporter that actively transports D-glucose at the plasma membrane, with a Na+ to sugar coupling ratio of 1:1. Transporter activity is driven by a transmembrane Na+ electrochemical gradient set by the Na+/K+ pump |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Sodium/glucose cotransporter 2
Macromolecule | Name: Sodium/glucose cotransporter 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 73.247703 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: GPGSMEEHTE AGSAPEMGAQ KALIDNPADI LVIAAYFLLV IGVGLWSMCR TNRGTVGGYF LAGRSMVWWP VGASLFASNI GSGHFVGLA GTGAASGLAV AGFEWNALFV VLLLGWLFAP VYLTAGVITM PQYLRKRFGG RRIRLYLSVL SLFLYIFTKI S VDMFSGAV ...String: GPGSMEEHTE AGSAPEMGAQ KALIDNPADI LVIAAYFLLV IGVGLWSMCR TNRGTVGGYF LAGRSMVWWP VGASLFASNI GSGHFVGLA GTGAASGLAV AGFEWNALFV VLLLGWLFAP VYLTAGVITM PQYLRKRFGG RRIRLYLSVL SLFLYIFTKI S VDMFSGAV FIQQALGWNI YASVIALLGI TMIYTVTGGL AALMYTDTVQ TFVILGGACI LMGYAFHEVG GYSGLFDKYL GA ATSLTVS EDPAVGNISS FCYRPRPDSY HLLRHPVTGD LPWPALLLGL TIVSGWYWCS DQVIVQRCLA GKSLTHIKAG CIL CGYLKL TPMFLMVMPG MISRILYPDE VACVVPEVCR RVCGTEVGCS NIAYPRLVVK LMPNGLRGLM LAVMLAALMS SLAS IFNSS STLFTMDIYT RLRPRAGDRE LLLVGRLWVV FIVVVSVAWL PVVQAAQGGQ LFDYIQAVSS YLAPPVSAVF VLALF VPRV NEQGAFWGLI GGLLMGLARL IPEFSFGSGS CVQPSACPAF LCGVHYLYFA IVLFFCSGLL TLTVSLCTAP IPRKHL HRL VFSLRHSKEE REDLDADEQQ GSSLPVQNGC PESAMEMNEP QAPAPSLFRQ CLLWFCGMSR GGVGSPPPLT QEEAAAA AR RLEDISEDPS WARVVNLNAL LMMAVAVFLW GFYA UniProtKB: Sodium/glucose cotransporter 2 |
-Macromolecule #2: PDZK1-interacting protein 1
Macromolecule | Name: PDZK1-interacting protein 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 12.235 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MSALSLLILG LLTAVPPASC QQGLGNLQPW MQGLIAVAVF LVLVAIAFAV NHFWCQEEPE PAHMILTVGN KADGVLVGTD GRYSSMAAS FRSSEHENAY ENVPEEEGKV RSTPM UniProtKB: PDZK1-interacting protein 1 |
-Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 1 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Macromolecule #4: (2S,3R,4R,5S,6R)-2-[4-chloranyl-3-[(4-ethoxyphenyl)methyl]phenyl]...
Macromolecule | Name: (2S,3R,4R,5S,6R)-2-[4-chloranyl-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol type: ligand / ID: 4 / Number of copies: 1 / Formula: LE6 |
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Molecular weight | Theoretical: 408.873 Da |
Chemical component information | ![]() ChemComp-LE6: |
-Macromolecule #5: SODIUM ION
Macromolecule | Name: SODIUM ION / type: ligand / ID: 5 / Number of copies: 1 |
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Molecular weight | Theoretical: 22.99 Da |
-Macromolecule #6: water
Macromolecule | Name: water / type: ligand / ID: 6 / Number of copies: 4 / 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
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 64.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |