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- PDB-8jy6: Structure of TbAQP2 in complex with anti-trypanosomatid drug mela... -

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Basic information

Entry
Database: PDB / ID: 8jy6
TitleStructure of TbAQP2 in complex with anti-trypanosomatid drug melarsoprol
ComponentsAquaglyceroporin 2
KeywordsMEMBRANE PROTEIN / Aquaporin
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
: / Aquaglyceroporin-2
Similarity search - Component
Biological speciesTrypanosoma brucei brucei (eukaryote)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsChen, W. / Wang, C.
Funding support China, 1items
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, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0May 29, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Aquaglyceroporin 2
B: Aquaglyceroporin 2
C: Aquaglyceroporin 2
D: Aquaglyceroporin 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)148,6978
Polymers147,1044
Non-polymers1,5934
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Aquaglyceroporin 2


Mass: 36775.914 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: Author stated: Residues from 313 to 343 are twin-strep tags for affinity purification.
Source: (gene. exp.) Trypanosoma brucei brucei (eukaryote) / Gene: aqp2 / Production host: Homo sapiens (human) / References: UniProt: Q6ZXT3
#2: Chemical
ChemComp-L1U / [(4~{R})-2-[4-[[4,6-bis(azanyl)-1,3,5-triazin-2-yl]amino]phenyl]-1,3,2-dithiarsolan-4-yl]methanol


Mass: 398.339 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H15AsN6OS2 / Feature type: SUBJECT OF INVESTIGATION
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: TbAQP2 complex with melarsorpol / Type: COMPLEX / Entity ID: #1 / 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 / Humidity: 100 %

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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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 71 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
2SerialEMimage acquisition
10cryoSPARCV2initial Euler assignment
11cryoSPARCV2final Euler assignment
13cryoSPARCv23D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 379082 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037616
ELECTRON MICROSCOPYf_angle_d0.55710396
ELECTRON MICROSCOPYf_dihedral_angle_d3.6121048
ELECTRON MICROSCOPYf_chiral_restr0.0361152
ELECTRON MICROSCOPYf_plane_restr0.0061300

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