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- PDB-9lht: Cryo-EM structure of inhibitor E3 bound human urea transporter A2. -

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Basic information

Entry
Database: PDB / ID: 9lht
TitleCryo-EM structure of inhibitor E3 bound human urea transporter A2.
ComponentsUrea transporter 2
KeywordsMEMBRANE PROTEIN / Urea transporter
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
: / Urea transporter 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsHuang, S. / Liu, L. / Sun, J.
Funding support China, 1items
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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 13, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Urea transporter 2
B: Urea transporter 2
C: Urea transporter 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,5669
Polymers130,2593
Non-polymers2,3066
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 Urea transporter 2 / Solute carrier family 14 member 2 / Urea transporter / kidney


Mass: 43419.789 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC14A2, HUT2, UT2
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: Q15849
#2: Chemical
ChemComp-A1EJ7 / 5-ethanoyl-~{N}-[3-(phenylsulfonylamino)phenyl]furan-2-carboxamide


Mass: 384.406 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C19H16N2O5S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: CELL / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Homotrimer complex of human urea transporter / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
Source (recombinant)Organism: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: FREON 12

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Electron microscopy imaging

Experimental equipment
Model: Tecnai Polara / Image courtesy: FEI Company
MicroscopyModel: FEI POLARA 300
Electron gunElectron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: OTHER / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON II (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 956530 / Symmetry type: POINT

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