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- EMDB-63105: Cryo-EM structure of inhibitor E3 bound human urea transporter A2. -

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Basic information

Entry
Database: EMDB / ID: EMD-63105
TitleCryo-EM structure of inhibitor E3 bound human urea transporter A2.
Map data
Sample
  • Complex: Homotrimer complex of human urea transporter
    • Protein or peptide: Urea transporter 2
  • Ligand: 5-ethanoyl-~{N}-[3-(phenylsulfonylamino)phenyl]furan-2-carboxamide
KeywordsUrea transporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


urea transport / Transport of bile salts and organic acids, metal ions and amine compounds / urea transmembrane transporter activity / urea transmembrane transport / cell adhesion molecule binding / transmembrane transport / apical plasma membrane / membrane / plasma membrane
Similarity search - Function
Urea transporter / Urea transporter / Ammonium/urea transporter
Similarity search - Domain/homology
Biological speciesSpodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsHuang S / Liu L / Sun J
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82304601 China
CitationJournal: Acta Pharmacol Sin / Year: 2025
Title: Structural characterization of the urea transporter bound to the orally bioavailable inhibitor E3.
Authors: Shen-Ming Huang / Bo-Yang Cai / Lei Liu / Le-Jin Yang / Zhi Li / Chao Zhang / Meng-Yao Xiong / Hang Zhang / Yan-Rong Li / Zhi-Zhen Huang / Ying Sun / Bao-Xue Yang / Jin-Peng Sun /
Abstract: Orally bioavailable inhibitors targeting the kidney urea transporter (UT) have the potential to serve as salt-sparing diuretics by employing a urea-selective diuretic mechanism of action distinct ...Orally bioavailable inhibitors targeting the kidney urea transporter (UT) have the potential to serve as salt-sparing diuretics by employing a urea-selective diuretic mechanism of action distinct from that of diuretics targeting salt transporters. To elucidate the mechanism by which oral inhibitors interact with UTs, we solved the structure of a newly developed inhibitor, E3, with UT-A2 using cryo-electron microscopy. Through structural analysis and binding free energy calculations, we not only revealed the binding mode of E3 to UT-A2 but also clarified the structural basis by which E3 serves as a common competitive inhibitor of human, mouse and rat UT-A/UT-B. E3 exerts its inhibitory effect by competitively binding to the conserved Q-T-T-Q motif in the urea binding pockets of the transport channel. Moreover, we discovered that the BSBP region of UT can serve as a key region for enhancing the inhibitory potency of E3 with different UTs, which provides valuable structural insights for designing and modifying high-affinity UT inhibitors that act as diuretics.
History
DepositionJan 13, 2025-
Header (metadata) releaseAug 13, 2025-
Map releaseAug 13, 2025-
UpdateAug 13, 2025-
Current statusAug 13, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_63105.png

Downloads & links

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Map

FileDownload / File: emd_63105.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 288 pix.
= 244.8 Å		0.85 Å/pix.
x 288 pix.
= 244.8 Å		0.85 Å/pix.
x 288 pix.
= 244.8 Å

Surface

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.17
Minimum - Maximum-0.8399587 - 1.2270559
Average (Standard dev.)0.0018441671 (±0.031110423)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 244.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_63105_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

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Histogram (log scale)

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Half map: #1

Fileemd_63105_half_map_2.map
Projections & Slices
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Sample components

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Entire : Homotrimer complex of human urea transporter

EntireName: Homotrimer complex of human urea transporter
Components
  • Complex: Homotrimer complex of human urea transporter
    • Protein or peptide: Urea transporter 2
  • Ligand: 5-ethanoyl-~{N}-[3-(phenylsulfonylamino)phenyl]furan-2-carboxamide

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Supramolecule #1: Homotrimer complex of human urea transporter

SupramoleculeName: Homotrimer complex of human urea transporter / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)

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Macromolecule #1: Urea transporter 2

MacromoleculeName: Urea transporter 2 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.419789 KDa
Recombinant expressionOrganism: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
SequenceString: MEESSEIKVE TNISKTSWIR SSMAASGKRV SKALSYITGE MKECGEGLKD KSPVFQFFDW VLRGTSQVMF VNNPLSGILI ILGLFIQNP WWAISGCLGT IMSTLTALIL SQDKSAIAAG FHGYNGVLVG LLMAVFSDKG DYYWWLLLPV IIMSMSCPIL S SALGTIFS ...String:
MEESSEIKVE TNISKTSWIR SSMAASGKRV SKALSYITGE MKECGEGLKD KSPVFQFFDW VLRGTSQVMF VNNPLSGILI ILGLFIQNP WWAISGCLGT IMSTLTALIL SQDKSAIAAG FHGYNGVLVG LLMAVFSDKG DYYWWLLLPV IIMSMSCPIL S SALGTIFS KWDLPVFTLP FNITVTLYLA ATGHYNLFFP TTLLQPASAM PNITWSEVQV PLLLRAIPVG IGQVYGCDNP WT GGIFLIA LFISSPLICL HAAIGSTMGM LAALTIATPF DSIYFGLCGF NSTLACIAIG GMFYVITWQT HLLAIACALF AAY LGAALA NMLSVFGLPP CTWPFCLSAL TFLLLTTNNP AIYKLPLSKV TYPEANRIYY LSQERNRRAS IITKYQAYDV S

UniProtKB: Urea transporter 2

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Macromolecule #2: 5-ethanoyl-~{N}-[3-(phenylsulfonylamino)phenyl]furan-2-carboxamide

MacromoleculeName: 5-ethanoyl-~{N}-[3-(phenylsulfonylamino)phenyl]furan-2-carboxamide
type: ligand / ID: 2 / Number of copies: 6 / Formula: A1EJ7
Molecular weightTheoretical: 384.406 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statecell

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: FREON 12

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Electron microscopy

MicroscopeFEI POLARA 300
Image recordingFilm or detector model: FEI FALCON II (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: OTHER
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: OTHER / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Tecnai Polara / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

3k3f

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 956530
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: OTHER

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