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- EMDB-36721: Structure of TbAQP2 in complex with anti-trypanosomatid drug mela... -

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Basic information

Entry
Database: EMDB / ID: EMD-36721
TitleStructure of TbAQP2 in complex with anti-trypanosomatid drug melarsoprol
Map data
Sample
  • Complex: TbAQP2 complex with melarsorpol
    • Protein or peptide: Aquaglyceroporin 2
  • Ligand: [(4~{R})-2-[4-[[4,6-bis(azanyl)-1,3,5-triazin-2-yl]amino]phenyl]-1,3,2-dithiarsolan-4-yl]methanol
KeywordsAquaporin / MEMBRANE PROTEIN
Function / homology
Function and homology information


glycerol channel activity / urea transmembrane transporter activity / glycerol transmembrane transport / urea transmembrane transport / water transport / water channel activity / membrane / plasma membrane
Similarity search - Function
: / Major intrinsic protein / Major intrinsic protein / Aquaporin-like
Similarity search - Domain/homology
Biological speciesHomo sapiens (human) / Trypanosoma brucei brucei (eukaryote)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.5 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-
UpdateJul 16, 2025-
Current statusJul 16, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36721.png

Downloads & links

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Map

FileDownload / File: emd_36721.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesX (Sec.)Y (Row.)Z (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

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.064 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.0
Minimum - Maximum-11.0699215 - 15.376644000000001
Average (Standard dev.)0.00006161326 (±0.27252352)
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: Author stated: The maps were generate from non-uniform...

Fileemd_36721_half_map_1.map
AnnotationAuthor stated: The maps were generate 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 (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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Histogram (log scale)

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Half map: #1

Fileemd_36721_half_map_2.map
Projections & Slices
AxesZYX

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Sample components

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Entire : TbAQP2 complex with melarsorpol

EntireName: TbAQP2 complex with melarsorpol
Components
  • Complex: TbAQP2 complex with melarsorpol
    • Protein or peptide: Aquaglyceroporin 2
  • Ligand: [(4~{R})-2-[4-[[4,6-bis(azanyl)-1,3,5-triazin-2-yl]amino]phenyl]-1,3,2-dithiarsolan-4-yl]methanol

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Supramolecule #1: TbAQP2 complex with melarsorpol

SupramoleculeName: TbAQP2 complex with melarsorpol / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Aquaglyceroporin 2

MacromoleculeName: Aquaglyceroporin 2 / type: protein_or_peptide / ID: 1
Details: Author stated: Residues from 313 to 343 are twin-strep tags for affinity purification.
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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Macromolecule #2: [(4~{R})-2-[4-[[4,6-bis(azanyl)-1,3,5-triazin-2-yl]amino]phenyl]-...

MacromoleculeName: [(4~{R})-2-[4-[[4,6-bis(azanyl)-1,3,5-triazin-2-yl]amino]phenyl]-1,3,2-dithiarsolan-4-yl]methanol
type: ligand / ID: 2 / Number of copies: 4 / Formula: L1U
Molecular weightTheoretical: 398.339 Da

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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

CTF correctionType: NONE
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v2) / Number images used: 379082
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC (ver. V2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. V2)

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