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- PDB-8c9h: AQP7_inhibitor -

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ID or keywords:

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Basic information

Entry
Database: PDB / ID: 8c9h
TitleAQP7_inhibitor
ComponentsAquaporin-7
KeywordsMEMBRANE PROTEIN / aquaglyceroporin / glycerol channel / dimer of tetramers / inhibitor
Function / homology
Function and homology information


Transport of glycerol from adipocytes to the liver by Aquaporins / glycerol channel activity / urea transmembrane transporter activity / Passive transport by Aquaporins / glycerol transmembrane transport / water transport / water channel activity / lipid droplet / cytoplasmic vesicle membrane / cell-cell junction ...Transport of glycerol from adipocytes to the liver by Aquaporins / glycerol channel activity / urea transmembrane transporter activity / Passive transport by Aquaporins / glycerol transmembrane transport / water transport / water channel activity / lipid droplet / cytoplasmic vesicle membrane / cell-cell junction / cell cortex / basolateral plasma membrane / plasma membrane / cytoplasm
Similarity search - Function
Major intrinsic protein / Major intrinsic protein / Aquaporin-like
Similarity search - Domain/homology
Chem-T60 / Aquaporin-7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsHuang, P. / Venskutonyte, R. / Gourdon, P. / Lindkvist-Petersson, K.
Funding support Sweden, 2items
OrganizationGrant numberCountry
Swedish Research Council2017-05816, 2016-01319 Sweden
Other governmentSwedish Cancer Society 20 0747 PjF Sweden
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: Molecular basis for human aquaporin inhibition.
Authors: Peng Huang / Hannah Åbacka / Carter J Wilson / Malene Lykke Wind / Michael Rűtzler / Anna Hagström-Andersson / Pontus Gourdon / Bert L de Groot / Raminta Venskutonytė / Karin Lindkvist-Petersson /
Abstract: Cancer invasion and metastasis are known to be potentiated by the expression of aquaporins (AQPs). Likewise, the expression levels of AQPs have been shown to be prognostic for survival in patients ...Cancer invasion and metastasis are known to be potentiated by the expression of aquaporins (AQPs). Likewise, the expression levels of AQPs have been shown to be prognostic for survival in patients and have a role in tumor growth, edema, angiogenesis, and tumor cell migration. Thus, AQPs are key players in cancer biology and potential targets for drug development. Here, we present the single-particle cryo-EM structure of human AQP7 at 3.2-Å resolution in complex with the specific inhibitor compound Z433927330. The structure in combination with MD simulations shows that the inhibitor binds to the endofacial side of AQP7. In addition, cancer cells treated with Z433927330 show reduced proliferation. The data presented here serve as a framework for the development of AQP inhibitors.
History
DepositionJan 22, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 31, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Mar 6, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Aquaporin-7
B: Aquaporin-7
C: Aquaporin-7
D: Aquaporin-7
E: Aquaporin-7
F: Aquaporin-7
G: Aquaporin-7
H: Aquaporin-7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)301,03016
Polymers298,1158
Non-polymers2,9158
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area30480 Å2
ΔGint-310 kcal/mol
Surface area69510 Å2
MethodPISA

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Components

#1: Protein
Aquaporin-7 / AQP-7 / Aquaglyceroporin-7 / Aquaporin adipose / AQPap / Aquaporin-7-like


Mass: 37264.395 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Details: LIG represents the inhibitor / Source: (gene. exp.) Homo sapiens (human) / Gene: AQP7, AQP7L, AQP9 / Production host: Komagataella pastoris (fungus) / References: UniProt: O14520
#2: Chemical
ChemComp-T60 / ethyl 4-[(4-pyrazol-1-ylphenyl)methylcarbamoylamino]benzoate / ethyl 4-(3-(4-(1H-pyrazol-1-yl)benzyl)ureido)benzoate


Mass: 364.398 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C20H20N4O3 / 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: AQP7 dimer of tetramers with inhibitor / Type: COMPLEX / Details: sample was prepared in GDN detergent / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Komagataella pastoris (fungus)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMsodium phosphateNa3PO41
2100 mMsodium chlorideNaCl1
30.01 %GDNC56H92O21
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: 25uM inhibitor was supplemented into protein solution before grid freezing.
Specimen supportDetails: 20mA for glow discharge / Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK II / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K / Details: 3s blot, 3s wait, 0s drain time, 0 blot force

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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 magnification: 105000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 600 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN
Image recordingAverage exposure time: 2.16 sec. / Electron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 9002

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Processing

EM software
IDNameVersionCategoryDetails
1cryoSPARCv3.2particle selection
2EPU2.11.1image acquisitionautomated faster aquisition
4cryoSPARCv3.2CTF correction
7UCSF Chimera1.15model fitting
11cryoSPARCclassification
12cryoSPARCv3.23D reconstruction
13PHENIX1.20.1-4487model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 484660 / Details: applying template picking tool.
SymmetryPoint symmetry: D4 (2x4 fold dihedral)
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 16851 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingB value: 108 / Protocol: RIGID BODY FIT / Space: REAL
Details: Initial model (PDB ID:8AMX) was fitted locally into map by Chimera.
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00216248
ELECTRON MICROSCOPYf_angle_d0.48422120
ELECTRON MICROSCOPYf_dihedral_angle_d7.0752200
ELECTRON MICROSCOPYf_chiral_restr0.0362440
ELECTRON MICROSCOPYf_plane_restr0.0042752

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