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- EMDB-38274: Cryo-EM structure of human urea transporter A2. -

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Basic information

Entry
Database: EMDB / ID: EMD-38274
TitleCryo-EM structure of human urea transporter A2.
Map data
Sample
  • Complex: Homotrimer complex of human urea transporter
    • Protein or peptide: Urea transporter 2
  • Ligand: 8-hydroxyquinoline-2-carboxylic acid
  • Ligand: 1-(3-methoxyphenyl)methanamine
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 speciesHomo sapiens (human) / Homo sapien (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: 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, 2023-
Header (metadata) releaseDec 4, 2024-
Map releaseDec 4, 2024-
UpdateDec 4, 2024-
Current statusDec 4, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38274.png

Downloads & links

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Map

FileDownload / File: emd_38274.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.)
0.82 Å/pix.
x 288 pix.
= 236.16 Å		0.82 Å/pix.
x 288 pix.
= 236.16 Å		0.82 Å/pix.
x 288 pix.
= 236.16 Å

Surface

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.18980123 - 0.44839147
Average (Standard dev.)0.0012695713 (±0.015167893)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 236.16 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_38274_half_map_1.map
Projections & Slices
AxesZYX

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Half map: #1

Fileemd_38274_half_map_2.map
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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: 8-hydroxyquinoline-2-carboxylic acid
  • Ligand: 1-(3-methoxyphenyl)methanamine

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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: Homo sapiens (human)

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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 sapien (human)
Molecular weightTheoretical: 43.419789 KDa
Recombinant expressionOrganism: Spodoptera (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: 8-hydroxyquinoline-2-carboxylic acid

MacromoleculeName: 8-hydroxyquinoline-2-carboxylic acid / type: ligand / ID: 2 / Number of copies: 3 / Formula: 8HC
Molecular weightTheoretical: 189.167 Da
Chemical component information

ChemComp-8HC:
8-hydroxyquinoline-2-carboxylic acid

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Macromolecule #3: 1-(3-methoxyphenyl)methanamine

MacromoleculeName: 1-(3-methoxyphenyl)methanamine / type: ligand / ID: 3 / Number of copies: 3 / Formula: SZ4
Molecular weightTheoretical: 137.179 Da
Chemical component information

ChemComp-SZ4:
1-(3-methoxyphenyl)methanamine

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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 TITAN KRIOS
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: Titan Krios / Image courtesy: FEI Company

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Image processing

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: 92767
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: OTHER

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