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- EMDB-36723: Structure of TbAQP2 in complex with anti-trypanosomatid drug pent... -

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Basic information

Entry
Database: EMDB / ID: EMD-36723
TitleStructure of TbAQP2 in complex with anti-trypanosomatid drug pentamidine
Map data
Sample
  • Complex: TbAQP2 complex with pentamidine
    • Protein or peptide: Aquaglyceroporin 2
  • Ligand: 1,5-BIS(4-AMIDINOPHENOXY)PENTANE
KeywordsAquaporin / MEMBRANE PROTEIN
Function / homologyglycerol channel activity / urea transmembrane transporter activity / water channel activity / Major intrinsic protein / Major intrinsic protein / Aquaporin-like / membrane / Aquaglyceroporin 2
Function and homology information
Biological speciesTrypanosoma brucei brucei (eukaryote)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.45 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_36723.png

Downloads & links

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Map

FileDownload / File: emd_36723.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.064 Å
Density
Contour LevelBy AUTHOR: 1.0
Minimum - Maximum-10.90381 - 16.163844999999998
Average (Standard dev.)0.000038750954 (±0.26047602)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
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: #2

Fileemd_36723_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_36723_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : TbAQP2 complex with pentamidine

EntireName: TbAQP2 complex with pentamidine
Components
  • Complex: TbAQP2 complex with pentamidine
    • Protein or peptide: Aquaglyceroporin 2
  • Ligand: 1,5-BIS(4-AMIDINOPHENOXY)PENTANE

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Supramolecule #1: TbAQP2 complex with pentamidine

SupramoleculeName: TbAQP2 complex with pentamidine / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
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: 33.614645 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 YFLPH

UniProtKB: Aquaglyceroporin 2

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Macromolecule #2: 1,5-BIS(4-AMIDINOPHENOXY)PENTANE

MacromoleculeName: 1,5-BIS(4-AMIDINOPHENOXY)PENTANE / type: ligand / ID: 2 / Number of copies: 4 / Formula: PNT
Molecular weightTheoretical: 340.419 Da
Chemical component information

ChemComp-PNT:
1,5-BIS(4-AMIDINOPHENOXY)PENTANE / medication, Antimicrobial*YM

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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: 2.45 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v2) / Number images used: 539330
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC (ver. V2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. V2)

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