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- EMDB-36722: Structure of the TbAQP2 in the apo conformation -

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Basic information

Entry
Database: EMDB / ID: EMD-36722
TitleStructure of the TbAQP2 in the apo conformation
Map data
Sample
  • Complex: Tetramer of TbAQP2
    • Protein or peptide: Aquaglyceroporin 2
KeywordsAquaporin / MEMBRANE PROTEIN
Function / homology
Function and homology information


glycerol channel activity / urea transmembrane transporter activity / urea transmembrane transport / glycerol transmembrane transport / water transport / water channel activity / membrane
Similarity search - Function
: / Major intrinsic protein / Major intrinsic protein / Aquaporin-like
Similarity search - Domain/homology
Biological speciesTrypanosoma brucei brucei (eukaryote)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsChen W / Wang C
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2024
Title: Structural insights into drug transport by an aquaglyceroporin.
Authors: Wanbiao Chen / Rongfeng Zou / Yi Mei / Jiawei Li / Yumi Xuan / Bing Cui / Junjie Zou / Juncheng Wang / Shaoquan Lin / Zhe Zhang / Chongyuan Wang /
Abstract: Pentamidine and melarsoprol are primary drugs used to treat the lethal human sleeping sickness caused by the parasite Trypanosoma brucei. Cross-resistance to these two drugs has recently been linked ...Pentamidine and melarsoprol are primary drugs used to treat the lethal human sleeping sickness caused by the parasite Trypanosoma brucei. Cross-resistance to these two drugs has recently been linked to aquaglyceroporin 2 of the trypanosome (TbAQP2). TbAQP2 is the first member of the aquaporin family described as capable of drug transport; however, the underlying mechanism remains unclear. Here, we present cryo-electron microscopy structures of TbAQP2 bound to pentamidine or melarsoprol. Our structural studies, together with the molecular dynamic simulations, reveal the mechanisms shaping substrate specificity and drug permeation. Multiple amino acids in TbAQP2, near the extracellular entrance and inside the pore, create an expanded conducting tunnel, sterically and energetically allowing the permeation of pentamidine and melarsoprol. Our study elucidates the mechanism of drug transport by TbAQP2, providing valuable insights to inform the design of drugs against trypanosomiasis.
History
DepositionJul 3, 2023-
Header (metadata) releaseMay 29, 2024-
Map releaseMay 29, 2024-
UpdateMay 29, 2024-
Current statusMay 29, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36722.png

Downloads & links

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Map

FileDownload / File: emd_36722.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.)
1.06 Å/pix.
x 256 pix.
= 272.384 Å		1.06 Å/pix.
x 256 pix.
= 272.384 Å		1.06 Å/pix.
x 256 pix.
= 272.384 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.064 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.6
Minimum - Maximum-6.784339 - 11.296426
Average (Standard dev.)0.00004807586 (±0.18477827)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 272.384 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_36722_half_map_1.map
Projections & Slices
AxesZYX

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Half map: Author stated: The maps were generated from non-uniform...

Fileemd_36722_half_map_2.map
AnnotationAuthor stated: The maps were generated from non-uniform refinement in cryosparc, an algorithm based on cross-validation optimization, which automatically regularizes 3D density maps during refinement to account for spatial variability. Unlike common shift-invariant regularizers, non-uniform refinement systematically removes noise from disordered regions, while retaining signal useful for aligning particle images, yielding dramatically improved resolution and 3D map quality in many cases, especially for membrane proteins (Nature methods 17.12 (2020): 1214-1221; https://www.nature.com/articles/s41592-020-00990-8). That is why the raw maps look like filtered.
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Tetramer of TbAQP2

EntireName: Tetramer of TbAQP2
Components
  • Complex: Tetramer of TbAQP2
    • Protein or peptide: Aquaglyceroporin 2

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Supramolecule #1: Tetramer of TbAQP2

SupramoleculeName: Tetramer of TbAQP2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Trypanosoma brucei brucei (eukaryote)

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Macromolecule #1: Aquaglyceroporin 2

MacromoleculeName: Aquaglyceroporin 2 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Trypanosoma brucei brucei (eukaryote)
Molecular weightTheoretical: 36.775914 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MQSQPDNVAY PMELQAVNKD GTVEVRVQGN VDNSSNERWD ADVQKHEVAE AQEKPVGGIN FWAPRELRLN YRDYVAEFLG NFVLIYIAK GAVITSLLVP DFGLLGLTIG IGVAVTMALY VSLGISGGHL NSAVTVGNAV FGDFPWRKVP GYIAAQMLGT F LGAACAYG ...String:
MQSQPDNVAY PMELQAVNKD GTVEVRVQGN VDNSSNERWD ADVQKHEVAE AQEKPVGGIN FWAPRELRLN YRDYVAEFLG NFVLIYIAK GAVITSLLVP DFGLLGLTIG IGVAVTMALY VSLGISGGHL NSAVTVGNAV FGDFPWRKVP GYIAAQMLGT F LGAACAYG VFADLLKAHG GGELIAFGEK GIAWVFAMYP AEGNGIFYPI FAELISTAVL LLCVCGIFDP NNSPAKGYET VA IGALVFV MVNNFGLASP LAMNPSLDFG PRVFGAILLG GEVFSHANYY FWVPLVVPFF GAILGLFLYK YFLPHSNSWS HPQ FEKGGG SGGGSGGSAW SHPQFEK

UniProtKB: Aquaglyceroporin-2

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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 / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 71.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 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: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v2) / Number images used: 153589
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC (ver. V2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. V2)

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