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- EMDB-34737: Structure of human SGLT2-MAP17 complex with Sotagliflozin -

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Basic information

Entry
Database: EMDB / ID: EMD-34737
TitleStructure of human SGLT2-MAP17 complex with Sotagliflozin
Map data
Sample
  • Complex: Binary complex of Sodium/glucose cotransporter 2 with PDZK1-interacting protein 1.
    • Protein or peptide: Sodium/glucose cotransporter 2
    • Protein or peptide: PDZK1-interacting protein 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (2S,3R,4R,5S,6R)-2-[4-chloranyl-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylsulfanyl-oxane-3,4,5-triol
  • Ligand: SODIUM ION
  • Ligand: water
KeywordsIon transport / Sodium transport / Sugar transport / Symport / Transport / TRANSPORT PROTEIN
Function / homology
Function and homology information


low-affinity D-glucose:sodium symporter activity / Defective SLC5A2 causes renal glucosuria (GLYS1) / alpha-glucoside transport / D-glucose:sodium symporter activity / alpha-glucoside transmembrane transporter activity / hexose transmembrane transport / D-glucose transmembrane transporter activity / renal D-glucose absorption / Cellular hexose transport / D-glucose import across plasma membrane ...low-affinity D-glucose:sodium symporter activity / Defective SLC5A2 causes renal glucosuria (GLYS1) / alpha-glucoside transport / D-glucose:sodium symporter activity / alpha-glucoside transmembrane transporter activity / hexose transmembrane transport / D-glucose transmembrane transporter activity / renal D-glucose absorption / Cellular hexose transport / D-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
PDZK1-interacting protein 1/SMIM24 / Membrane-associated protein 117 kDa, PDZK1-interacting protein 1 / Sodium:solute symporter family signature 2. / Sodium:solute symporter family signature 1. / Sodium/solute symporter, conserved site / Sodium/solute symporter / Sodium/glucose symporter superfamily / Sodium:solute symporter family / Sodium:solute symporter family profile.
Similarity search - Domain/homology
Sodium/glucose cotransporter 2 / PDZK1-interacting protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsHiraizumi M / Kishida H / Miyaguchi I / Nureki O
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: Nat Struct Mol Biol / Year: 2024
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
DepositionNov 14, 2022-
Header (metadata) releaseNov 15, 2023-
Map releaseNov 15, 2023-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_34737.png

Downloads & links

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Map

FileDownload / File: emd_34737.map.gz / Format: CCP4 / Size: 6.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.11 Å/pix.
x 120 pix.
= 132.8 Å		1.11 Å/pix.
x 120 pix.
= 132.8 Å		1.11 Å/pix.
x 120 pix.
= 132.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.10667 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0364
Minimum - Maximum-0.13333294 - 0.21623182
Average (Standard dev.)0.0007753116 (±0.009838651)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions120120120
Spacing120120120
CellA=B=C: 132.8004 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_34737_msk_1.map
Projections & Slices
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Half map: #2

Fileemd_34737_half_map_1.map
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Half map: #1

Fileemd_34737_half_map_2.map
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Sample components

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Entire : Binary complex of Sodium/glucose cotransporter 2 with PDZK1-inter...

EntireName: Binary complex of Sodium/glucose cotransporter 2 with PDZK1-interacting protein 1.
Components
  • Complex: Binary complex of Sodium/glucose cotransporter 2 with PDZK1-interacting protein 1.
    • Protein or peptide: Sodium/glucose cotransporter 2
    • Protein or peptide: PDZK1-interacting protein 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (2S,3R,4R,5S,6R)-2-[4-chloranyl-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylsulfanyl-oxane-3,4,5-triol
  • Ligand: SODIUM ION
  • Ligand: water

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Supramolecule #1: Binary complex of Sodium/glucose cotransporter 2 with PDZK1-inter...

SupramoleculeName: 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
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sodium/glucose cotransporter 2

MacromoleculeName: Sodium/glucose cotransporter 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 73.247703 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

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Macromolecule #2: PDZK1-interacting protein 1

MacromoleculeName: PDZK1-interacting protein 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.235 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MSALSLLILG LLTAVPPASC QQGLGNLQPW MQGLIAVAVF LVLVAIAFAV NHFWCQEEPE PAHMILTVGN KADGVLVGTD GRYSSMAAS FRSSEHENAY ENVPEEEGKV RSTPM

UniProtKB: PDZK1-interacting protein 1

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #4: (2S,3R,4R,5S,6R)-2-[4-chloranyl-3-[(4-ethoxyphenyl)methyl]phenyl]...

MacromoleculeName: (2S,3R,4R,5S,6R)-2-[4-chloranyl-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylsulfanyl-oxane-3,4,5-triol
type: ligand / ID: 4 / Number of copies: 1 / Formula: LFL
Molecular weightTheoretical: 424.938 Da
Chemical component information

ChemComp-LFL:
(2S,3R,4R,5S,6R)-2-[4-chloranyl-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylsulfanyl-oxane-3,4,5-triol

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Macromolecule #5: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 5 / Number of copies: 1
Molecular weightTheoretical: 22.99 Da

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 2 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 64.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination 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

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 72773
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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