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- EMDB-37868: The focused map of ACE2-SIT1 bound with tiagabine -

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Basic information

Entry
Database: EMDB / ID: EMD-37868
TitleThe focused map of ACE2-SIT1 bound with tiagabine
Map data
Sample
  • Complex: ACE2-SIT1 compelx with Tiagabine
KeywordsTransporter / inhibitors / TRANSPORT PROTEIN / TRANSPORT PROTEIN-HYDROLASE complex
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsYan R / Dai L / Hu Z / Zhang T
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32371267 China
CitationJournal: J Biol Chem / Year: 2024
Title: Cryo-EM structure of ACE2-SIT1 in complex with tiagabine.
Authors: Angelika Bröer / Ziwei Hu / Jędrzej Kukułowicz / Aditya Yadav / Ting Zhang / Lu Dai / Marek Bajda / Renhong Yan / Stefan Bröer /
Abstract: The pharmacology of amino acid transporters in the SLC6 family is poorly developed compared to that of the neurotransmitter transporters. To identify new inhibitors of the proline transporter SIT1 ...The pharmacology of amino acid transporters in the SLC6 family is poorly developed compared to that of the neurotransmitter transporters. To identify new inhibitors of the proline transporter SIT1 (SLC6A20), its expression in Xenopus laevis oocytes was optimized. Trafficking of SIT1 was augmented by co-expression of angiotensin-converting enzyme 2 (ACE2) in oocytes but there was no strict requirement for co-expression of ACE2. A pharmacophore-guided screen identified tiagabine as a potent non-competitive inhibitor of SIT1. To understand its binding mode, we determined the cryo-electron microscopy (cryo-EM) structure of ACE2-SIT1 bound with tiagabine. The inhibitor binds close to the orthosteric proline binding site, but due to its size extends into the cytosolic vestibule. This causes the transporter to adopt an inward-open conformation, in which the intracellular gate is blocked. This study provides the first structural insight into inhibition of SIT1 and generates tools for a better understanding of the ACE2-SIT1 complex. These findings may have significance for SARS-CoV-2 binding to its receptor ACE2 in human lung alveolar cells where SIT1 and ACE2 are functionally expressed.
History
DepositionOct 24, 2023-
Header (metadata) releaseSep 25, 2024-
Map releaseSep 25, 2024-
UpdateSep 25, 2024-
Current statusSep 25, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37868.png

Downloads & links

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Map

FileDownload / File: emd_37868.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 256 pix.
= 280.32 Å		1.1 Å/pix.
x 256 pix.
= 280.32 Å		1.1 Å/pix.
x 256 pix.
= 280.32 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.095 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.17
Minimum - Maximum-4.661202 - 4.8754926
Average (Standard dev.)0.009573851 (±0.06224275)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 280.32 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_37868_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_37868_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : ACE2-SIT1 compelx with Tiagabine

EntireName: ACE2-SIT1 compelx with Tiagabine
Components
  • Complex: ACE2-SIT1 compelx with Tiagabine

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Supramolecule #1: ACE2-SIT1 compelx with Tiagabine

SupramoleculeName: ACE2-SIT1 compelx with Tiagabine / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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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: NITROGEN

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.059 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 0.8 µm / Nominal defocus min: 0.7000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

30040

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 193320
Initial angle assignmentType: COMMON LINE
Final angle assignmentType: COMMON LINE

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