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- EMDB-16510: AQP7_inhibitor -

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Basic information

Entry
Database: EMDB / ID: EMD-16510
TitleAQP7_inhibitor
Map data
Sample
  • Complex: AQP7 dimer of tetramers with inhibitor
    • Protein or peptide: Aquaporin-7
  • Ligand: ethyl 4-[(4-pyrazol-1-ylphenyl)methylcarbamoylamino]benzoate
Keywordsaquaglyceroporin / glycerol channel / dimer of tetramers / inhibitor / MEMBRANE PROTEIN
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
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsHuang P / Venskutonyte R / Gourdon P / Lindkvist-Petersson K
Funding support Sweden, 2 items
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, 2023-
Header (metadata) releaseJan 31, 2024-
Map releaseJan 31, 2024-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16510.png

Downloads & links

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Map

FileDownload / File: emd_16510.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 300 pix.
= 253.92 Å		0.85 Å/pix.
x 300 pix.
= 253.92 Å		0.85 Å/pix.
x 300 pix.
= 253.92 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8464 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.49006283 - 0.8120172
Average (Standard dev.)0.00289562 (±0.03168857)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 253.92001 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_16510_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

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Half map: #2

Fileemd_16510_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_16510_half_map_2.map
Projections & Slices
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Sample components

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Entire : AQP7 dimer of tetramers with inhibitor

EntireName: AQP7 dimer of tetramers with inhibitor
Components
  • Complex: AQP7 dimer of tetramers with inhibitor
    • Protein or peptide: Aquaporin-7
  • Ligand: ethyl 4-[(4-pyrazol-1-ylphenyl)methylcarbamoylamino]benzoate

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Supramolecule #1: AQP7 dimer of tetramers with inhibitor

SupramoleculeName: AQP7 dimer of tetramers with inhibitor / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: sample was prepared in GDN detergent
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Aquaporin-7

MacromoleculeName: Aquaporin-7 / type: protein_or_peptide / ID: 1 / Details: LIG represents the inhibitor / Number of copies: 8 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.264395 KDa
Recombinant expressionOrganism: Komagataella pastoris (fungus)
SequenceString: MVQASGHRRS TRGSKMVSWS VIAKIQEILQ RKMVREFLAE FMSTYVMMVF GLGSVAHMVL NKKYGSYLGV NLGFGFGVTM GVHVAGRIS GAHMNAAVTF ANCALGRVPW RKFPVYVLGQ FLGSFLAAAT IYSLFYTAIL HFSGGQLMVT GPVATAGIFA T YLPDHMTL ...String:
MVQASGHRRS TRGSKMVSWS VIAKIQEILQ RKMVREFLAE FMSTYVMMVF GLGSVAHMVL NKKYGSYLGV NLGFGFGVTM GVHVAGRIS GAHMNAAVTF ANCALGRVPW RKFPVYVLGQ FLGSFLAAAT IYSLFYTAIL HFSGGQLMVT GPVATAGIFA T YLPDHMTL WRGFLNEAWL TGMLQLCLFA ITDQENNPAL PGTEALVIGI LVVIIGVSLG MNTGYAINPS RDLPPRIFTF IA GWGKQVF SNGENWWWVP VVAPLLGAYL GGIIYLVFIG STIPREPLKL EDSVAYEDHG ITVLPKMGSH EPTISPLTPV SVS PANRSS VHPAPPLHES MALEHF

UniProtKB: Aquaporin-7

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Macromolecule #2: ethyl 4-[(4-pyrazol-1-ylphenyl)methylcarbamoylamino]benzoate

MacromoleculeName: ethyl 4-[(4-pyrazol-1-ylphenyl)methylcarbamoylamino]benzoate
type: ligand / ID: 2 / Number of copies: 8 / Formula: T60
Molecular weightTheoretical: 364.398 Da
Chemical component information

ChemComp-T60:
ethyl 4-[(4-pyrazol-1-ylphenyl)methylcarbamoylamino]benzoate

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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

Concentration1 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
20.0 mMNa3PO4sodium phosphate
100.0 mMNaClsodium chloride
0.01 %C56H92O2GDN
GridModel: C-flat-1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Details: 20mA for glow discharge
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK II / Details: 3s blot, 3s wait, 0s drain time, 0 blot force.
Details25uM inhibitor was supplemented into protein solution before grid freezing.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 9002 / Average exposure time: 2.16 sec. / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 105000
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 484660 / Details: applying template picking tool.
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8amx

Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: D4 (2x4 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v3.2) / Number images used: 16851
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 5 / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

DetailsInitial model (PDB ID:8AMX) was fitted locally into map by Chimera.
RefinementSpace: REAL / Protocol: RIGID BODY FIT / Overall B value: 108
Output model

PDB-8c9h:
AQP7_inhibitor

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