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- PDB-7wmv: Structure of human SGLT1-MAP17 complex bound with LX2761 -

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Basic information

Entry
Database: PDB / ID: 7wmv
TitleStructure of human SGLT1-MAP17 complex bound with LX2761
Components
  • PDZK1-interacting protein 1
  • Sodium/glucose cotransporter 1
KeywordsPROTEIN TRANSPORT / glucose transporter / SGLT / sodium glucose transporter / membrane protein
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 / myo-inositol transport / intestinal hexose absorption / Defective SLC5A1 causes congenital glucose/galactose malabsorption (GGM) / Intestinal hexose absorption / fucose transmembrane transport ...myo-inositol:sodium symporter activity / pentose transmembrane transporter activity / fucose transmembrane transporter activity / galactose:sodium symporter activity / pentose transmembrane transport / myo-inositol transport / intestinal hexose absorption / Defective SLC5A1 causes congenital glucose/galactose malabsorption (GGM) / Intestinal hexose absorption / fucose transmembrane transport / intestinal D-glucose absorption / galactose transmembrane transporter activity / alpha-glucoside transport / D-glucose:sodium symporter activity / alpha-glucoside transmembrane transporter activity / galactose transmembrane transport / water transmembrane transporter activity / D-glucose transmembrane transporter activity / : / renal D-glucose absorption / Cellular hexose transport / D-glucose import across plasma membrane / D-glucose transmembrane transport / transepithelial water transport / intracellular organelle / sodium ion import across plasma membrane / intracellular vesicle / sodium ion transport / 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
Chem-1YI / Sodium/glucose cotransporter 1 / PDZK1-interacting protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsChen, L. / Niu, Y. / Cui, W.
Funding support China, 3items
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, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 16, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Sodium/glucose cotransporter 1
B: PDZK1-interacting protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)86,4253
Polymers85,8232
Non-polymers6021
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Sodium/glucose cotransporter 1 / Na(+)/glucose cotransporter 1 / High affinity sodium-glucose cotransporter / Solute carrier family 5 member 1


Mass: 73557.703 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC5A1, NAGT, SGLT1 / Production host: Homo sapiens (human) / References: UniProt: P13866
#2: Protein PDZK1-interacting protein 1 / 17 kDa membrane-associated protein / Protein DD96


Mass: 12265.092 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDZK1IP1, MAP17 / Production host: Homo sapiens (human) / References: UniProt: Q13113
#3: Chemical 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 / LX2761


Mass: 601.797 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H47N3O6S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: human SGLT1-MAP17 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM softwareName: cryoSPARC / Version: v3.1.0 / Category: 3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 12133 / Symmetry type: POINT

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