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- EMDB-32617: Structure of human SGLT1-MAP17 complex bound with LX2761 -

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Basic information

Entry
Database: EMDB / ID: EMD-32617
TitleStructure of human SGLT1-MAP17 complex bound with LX2761
Map dataSharpened map of human SGLT1-MAP17 complex with LX2761.
Sample
  • Complex: human SGLT1-MAP17 complex
    • Protein or peptide: Sodium/glucose cotransporter 1
    • Protein or peptide: PDZK1-interacting protein 1
  • Ligand: N-[2-(dimethylamino)ethyl]-2-methyl-2-[4-[4-[[2-methyl-5-[(2S,3R,4R,5S,6R)-6-methylsulfanyl-3,4,5-tris(oxidanyl)oxan-2-yl]phenyl]methyl]phenyl]butanoylamino]propanamide
Function / homology
Function and homology information


myo-inositol:sodium symporter activity / pentose transmembrane transporter activity / fucose transmembrane transporter activity / galactose:sodium symporter activity / pentose transmembrane transport / intestinal hexose absorption / Defective SLC5A1 causes congenital glucose/galactose malabsorption (GGM) / Intestinal hexose absorption / fucose transmembrane transport / myo-inositol transport ...myo-inositol:sodium symporter activity / pentose transmembrane transporter activity / fucose transmembrane transporter activity / galactose:sodium symporter activity / pentose transmembrane transport / intestinal hexose absorption / Defective SLC5A1 causes congenital glucose/galactose malabsorption (GGM) / Intestinal hexose absorption / fucose transmembrane transport / myo-inositol transport / intestinal D-glucose absorption / galactose transmembrane transporter activity / alpha-glucoside transport / alpha-glucoside transmembrane transporter activity / glucose:sodium symporter activity / galactose transmembrane transport / water transmembrane transporter activity / D-glucose transmembrane transporter activity / Cellular hexose transport / glucose transmembrane transporter activity / renal glucose absorption / glucose import across plasma membrane / glucose transmembrane transport / transepithelial water transport / intracellular organelle / sodium ion import across plasma membrane / sodium ion transport / intracellular vesicle / transport across blood-brain barrier / : / brush border membrane / early endosome / apical plasma membrane / perinuclear region of cytoplasm / 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 1 / PDZK1-interacting protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsChen L / Niu Y / Cui W
Funding support China, 3 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)91957201 China
National Natural Science Foundation of China (NSFC)31821091 China
National Natural Science Foundation of China (NSFC)31870833 China
CitationJournal: Nat Commun / Year: 2022
Title: Structural mechanism of SGLT1 inhibitors.
Authors: Yange Niu / Wenhao Cui / Rui Liu / Sanshan Wang / Han Ke / Xiaoguang Lei / Lei Chen /
Abstract: Sodium glucose co-transporters (SGLT) harness the electrochemical gradient of sodium to drive the uphill transport of glucose across the plasma membrane. Human SGLT1 (hSGLT1) plays a key role in ...Sodium glucose co-transporters (SGLT) harness the electrochemical gradient of sodium to drive the uphill transport of glucose across the plasma membrane. Human SGLT1 (hSGLT1) plays a key role in sugar uptake from food and its inhibitors show promise in the treatment of several diseases. However, the inhibition mechanism for hSGLT1 remains elusive. Here, we present the cryo-EM structure of the hSGLT1-MAP17 hetero-dimeric complex in the presence of the high-affinity inhibitor LX2761. LX2761 locks the transporter in an outward-open conformation by wedging inside the substrate-binding site and the extracellular vestibule of hSGLT1. LX2761 blocks the putative water permeation pathway of hSGLT1. The structure also uncovers the conformational changes of hSGLT1 during transitions from outward-open to inward-open states.
History
DepositionJan 17, 2022-
Header (metadata) releaseNov 16, 2022-
Map releaseNov 16, 2022-
UpdateNov 16, 2022-
Current statusNov 16, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_32617.png

Downloads & links

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Map

FileDownload / File: emd_32617.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map of human SGLT1-MAP17 complex with LX2761.
Voxel sizeX=Y=Z: 0.821 Å
Density
Contour LevelBy AUTHOR: 0.6
Minimum - Maximum-3.9103718 - 5.549981
Average (Standard dev.)-9.520257e-05 (±0.15477586)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 229.87999 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half-A map of human SGLT1-MAP17 complex with LX2761.

Fileemd_32617_half_map_1.map
AnnotationHalf-A map of human SGLT1-MAP17 complex with LX2761.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-B map of human SGLT1-MAP17 complex with LX2761.

Fileemd_32617_half_map_2.map
AnnotationHalf-B map of human SGLT1-MAP17 complex with LX2761.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human SGLT1-MAP17 complex

EntireName: human SGLT1-MAP17 complex
Components
  • Complex: human SGLT1-MAP17 complex
    • Protein or peptide: Sodium/glucose cotransporter 1
    • Protein or peptide: PDZK1-interacting protein 1
  • Ligand: N-[2-(dimethylamino)ethyl]-2-methyl-2-[4-[4-[[2-methyl-5-[(2S,3R,4R,5S,6R)-6-methylsulfanyl-3,4,5-tris(oxidanyl)oxan-2-yl]phenyl]methyl]phenyl]butanoylamino]propanamide

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Supramolecule #1: human SGLT1-MAP17 complex

SupramoleculeName: human SGLT1-MAP17 complex / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Sodium/glucose cotransporter 1

MacromoleculeName: Sodium/glucose cotransporter 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 73.557703 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDSSTWSPKT TAVTRPVETH ELIRNAADIS IIVIYFVVVM AVGLWAMFST NRGTVGGFFL AGRSMVWWPI GASLFASNIG SGHFVGLAG TGAASGIAIG GFEWNALVLV VVLGWLFVPI YIKAGVVTMP EYLRKRFGGQ RIQVYLSLLS LLLYIFTKIS A DIFSGAIF ...String:
MDSSTWSPKT TAVTRPVETH ELIRNAADIS IIVIYFVVVM AVGLWAMFST NRGTVGGFFL AGRSMVWWPI GASLFASNIG SGHFVGLAG TGAASGIAIG GFEWNALVLV VVLGWLFVPI YIKAGVVTMP EYLRKRFGGQ RIQVYLSLLS LLLYIFTKIS A DIFSGAIF INLALGLNLY LAIFLLLAIT ALYTITGGLA AVIYTDTLQT VIMLVGSLIL TGFAFHEVGG YDAFMEKYMK AI PTIVSDG NTTFQEKCYT PRADSFHIFR DPLTGDLPWP GFIFGMSILT LWYWCTDQVI VQRCLSAKNM SHVKGGCILC GYL KLMPMF IMVMPGMISR ILYTEKIACV VPSECEKYCG TKVGCTNIAY PTLVVELMPN GLRGLMLSVM LASLMSSLTS IFNS ASTLF TMDIYAKVRK RASEKELMIA GRLFILVLIG ISIAWVPIVQ SAQSGQLFDY IQSITSYLGP PIAAVFLLAI FWKRV NEPG AFWGLILGLL IGISRMITEF AYGTGSCMEP SNCPTIICGV HYLYFAIILF AISFITIVVI SLLTKPIPDV HLYRLC WSL RNSKEERIDL DAEEENIQEG PKETIEIETQ VPEKKKGIFR RAYDLFCGLE QHGAPKMTEE EEKAMKMKMT DTSEKPL WR TVLNVNGIIL VTVAVFCHAY FA

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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: 12.265092 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MSALSLLILG LLMAVPPASC QQGLGNLQPW MQGLIAVAVF LVLVAIAFAV NHFWCQEEPE PAHMILTVGN KADGVLVGTD GRYSSMAAS FRSSEHENAY ENVPEEEGKV RSTPM

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Macromolecule #3: N-[2-(dimethylamino)ethyl]-2-methyl-2-[4-[4-[[2-methyl-5-[(2S,3R,...

MacromoleculeName: N-[2-(dimethylamino)ethyl]-2-methyl-2-[4-[4-[[2-methyl-5-[(2S,3R,4R,5S,6R)-6-methylsulfanyl-3,4,5-tris(oxidanyl)oxan-2-yl]phenyl]methyl]phenyl]butanoylamino]propanamide
type: ligand / ID: 3 / Number of copies: 1 / Formula: 1YI
Molecular weightTheoretical: 601.797 Da
Chemical component information

ChemComp-1YI:
N-[2-(dimethylamino)ethyl]-2-methyl-2-[4-[4-[[2-methyl-5-[(2S,3R,4R,5S,6R)-6-methylsulfanyl-3,4,5-tris(oxidanyl)oxan-2-yl]phenyl]methyl]phenyl]butanoylamino]propanamide

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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 K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE / Details: ab initio
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v3.1.0) / Number images used: 12133
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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