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- PDB-8xdb: Cryo-EM structure of human urea transporter A2. -

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Basic information

Entry
Database: PDB / ID: 8xdb
TitleCryo-EM structure of 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: 3.3 Å
AuthorsHuang, S. / Liu, L. / Sun, J.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82304601 China
CitationJournal: Nat Commun / Year: 2024
Title: Structural insights into the mechanisms of urea permeation and distinct inhibition modes of urea transporters.
Authors: Shen-Ming Huang / Zhi-Zhen Huang / Lei Liu / Meng-Yao Xiong / Chao Zhang / Bo-Yang Cai / Ming-Wei Wang / Kui Cai / Ying-Li Jia / Jia-Le Wang / Ming-Hui Zhang / Yi-He Xie / Min Li / Hang ...Authors: Shen-Ming Huang / Zhi-Zhen Huang / Lei Liu / Meng-Yao Xiong / Chao Zhang / Bo-Yang Cai / Ming-Wei Wang / Kui Cai / Ying-Li Jia / Jia-Le Wang / Ming-Hui Zhang / Yi-He Xie / Min Li / Hang Zhang / Cheng-Hao Weng / Xin Wen / Zhi Li / Ying Sun / Fan Yi / Zhao Yang / Peng Xiao / Fan Yang / Xiao Yu / Lu Tie / Bao-Xue Yang / Jin-Peng Sun /
Abstract: Urea's transmembrane transport through urea transporters (UT) is a fundamental physiological behavior for life activities. Here, we present 11 cryo-EM structures of four UT members in resting states, ...Urea's transmembrane transport through urea transporters (UT) is a fundamental physiological behavior for life activities. Here, we present 11 cryo-EM structures of four UT members in resting states, urea transport states, or inactive states bound with synthetic competitive, uncompetitive or noncompetitive inhibitor. Our results indicate that the binding of urea via a conserved urea recognition motif (URM) and the urea transport via H-bond transfer along the Q-T-T-Q motif among different UT members. Moreover, distinct binding modes of the competitive inhibitors 25a and ATB3, the uncompetitive inhibitor CF11 and the noncompetitive inhibitor HQA2 provide different mechanisms for blocking urea transport and achieved selectivity through L-P pocket, UCBP region and SCG pocket, respectively. In summary, our study not only allows structural understanding of urea transport via UTs but also afforded a structural landscape of hUT-A2 inhibition by competitive, uncompetitive and noncompetitive inhibitors, which may facilitate developing selective human UT-A inhibitors as a new class of salt-sparing diuretics.
History
DepositionDec 10, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 4, 2024Provider: 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)131,8459
Polymers130,2593
Non-polymers1,5866
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 (butterflies/moths) / References: UniProt: Q15849
#2: Chemical
ChemComp-A1LYJ / (5E)-2-azanylidene-5-[(2,3-dimethoxyphenyl)methylidene]-1,3-thiazolidin-4-one


Mass: 264.300 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C12H12N2O3S / 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: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera (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: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
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: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 102413 / Symmetry type: POINT

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