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- PDB-7vsi: Structure of human SGLT2-MAP17 complex bound with empagliflozin -

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Basic information

Entry
Database: PDB / ID: 7vsi
TitleStructure of human SGLT2-MAP17 complex bound with empagliflozin
Components
  • PDZK1-interacting protein 1
  • Sodium/glucose cotransporter 2
KeywordsTRANSPORT PROTEIN / glucose transporter / SGLT2 / SGLT
Function / homology
Function and homology information


low-affinity glucose:sodium symporter activity / Defective SLC5A2 causes renal glucosuria (GLYS1) / alpha-glucoside transport / glucose:sodium symporter activity / alpha-glucoside transmembrane transporter 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 / glucose:sodium symporter activity / alpha-glucoside transmembrane transporter 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
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-7R3 / PALMITIC ACID / Sodium/glucose cotransporter 2 / PDZK1-interacting protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.95 Å
AuthorsChen, L. / Niu, Y. / Liu, R.
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: Nature / Year: 2022
Title: Structural basis of inhibition of the human SGLT2-MAP17 glucose transporter.
Authors: Yange Niu / Rui Liu / Chengcheng Guan / Yuan Zhang / Zhixing Chen / Stefan Hoerer / Herbert Nar / Lei Chen /
Abstract: Human sodium-glucose cotransporter 2 (hSGLT2) mediates the reabsorption of the majority of filtrated glucose in the kidney. Pharmacological inhibition of hSGLT2 by oral small-molecule inhibitors, ...Human sodium-glucose cotransporter 2 (hSGLT2) mediates the reabsorption of the majority of filtrated glucose in the kidney. Pharmacological inhibition of hSGLT2 by oral small-molecule inhibitors, such as empagliflozin, leads to enhanced excretion of glucose and is widely used in the clinic to manage blood glucose levels for the treatment of type 2 diabetes. Here we determined the cryogenic electron microscopy structure of the hSGLT2-MAP17 complex in the empagliflozin-bound state to an overall resolution of 2.95 Å. Our structure shows eukaryotic SGLT-specific structural features. MAP17 interacts with transmembrane helix 13 of hSGLT2. Empagliflozin occupies both the sugar-substrate-binding site and the external vestibule to lock hSGLT2 in an outward-open conformation, thus inhibiting the transport cycle. Our work provides a framework for understanding the mechanism of SLC5A family glucose transporters and also develops a foundation for the future rational design and optimization of new inhibitors targeting these transporters.
History
DepositionOct 26, 2021Deposition site: PDBJ / Processing site: PDBJ
SupersessionDec 15, 2021ID: 7FEN
Revision 1.0Dec 15, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 22, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Feb 16, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

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Assembly

Deposited unit
A: Sodium/glucose cotransporter 2
B: PDZK1-interacting protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,8505
Polymers78,8872
Non-polymers9643
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area1730 Å2
ΔGint-13 kcal/mol
Surface area24410 Å2
MethodPISA

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Components

#1: Protein Sodium/glucose cotransporter 2 / Na(+)/glucose cotransporter 2 / Low affinity sodium-glucose cotransporter / Solute carrier family 5 member 2


Mass: 72949.414 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC5A2, SGLT2 / Production host: Homo sapiens (human) / References: UniProt: P31639
#2: Protein PDZK1-interacting protein 1 / 17 kDa membrane-associated protein / Protein DD96


Mass: 5937.134 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-PLM / PALMITIC ACID / Palmitic acid


Mass: 256.424 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H32O2
#4: Chemical ChemComp-7R3 / (2S,3R,4R,5S,6R)-2-[4-chloranyl-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol / Empagliflozin / Empagliflozin


Mass: 450.909 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27ClO7 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
Has ligand of interestY

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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 SGLT2-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 FIELDBright-field microscopy
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM softwareName: RELION / Version: 3.1 / Category: 3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 2.95 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 36375 / Symmetry type: POINT

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