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- EMDB-16110: Human Urea Transporter UT-A (N-Terminal Domain Model) -

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Basic information

Entry
Database: EMDB / ID: EMD-16110
TitleHuman Urea Transporter UT-A (N-Terminal Domain Model)
Map data
Sample
  • Complex: Trimer-like complex of Human UT-A
    • Protein or peptide: Urea transporter 2
  • Ligand: di-heneicosanoyl phosphatidyl choline
  • Ligand: Lauryl Maltose Neopentyl Glycol
  • Ligand: water
KeywordsSLC14A2 / UT2 / UT-A / Urea Transporter / Inhibitor / Solute Carrier / TRANSPORT 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsChi G / Pike ACW / Maclean EM / Mukhopadhyay SMM / Bohstedt T / Scacioc A / Wang D / McKinley G / Fernandez-Cid A / Arrowsmith CH ...Chi G / Pike ACW / Maclean EM / Mukhopadhyay SMM / Bohstedt T / Scacioc A / Wang D / McKinley G / Fernandez-Cid A / Arrowsmith CH / Bountra C / Edwards A / Burgess-Brown NA / van Putte W / Duerr K
Funding support United Kingdom, European Union, 2 items
OrganizationGrant numberCountry
Wellcome Trust106169/Z/14/Z United Kingdom
European Union (EU)875510, 115766European Union
CitationJournal: Sci Adv / Year: 2023
Title: Structural characterization of human urea transporters UT-A and UT-B and their inhibition.
Authors: Gamma Chi / Larissa Dietz / Haiping Tang / Matthew Snee / Andreea Scacioc / Dong Wang / Gavin Mckinley / Shubhashish M M Mukhopadhyay / Ashley C W Pike / Rod Chalk / Nicola A Burgess-Brown / ...Authors: Gamma Chi / Larissa Dietz / Haiping Tang / Matthew Snee / Andreea Scacioc / Dong Wang / Gavin Mckinley / Shubhashish M M Mukhopadhyay / Ashley C W Pike / Rod Chalk / Nicola A Burgess-Brown / Jean-Pierre Timmermans / Wouter van Putte / Carol V Robinson / Katharina L Dürr /
Abstract: In this study, we present the structures of human urea transporters UT-A and UT-B to characterize them at molecular level and to detail the mechanism of UT-B inhibition by its selective inhibitor, ...In this study, we present the structures of human urea transporters UT-A and UT-B to characterize them at molecular level and to detail the mechanism of UT-B inhibition by its selective inhibitor, UTB-14. High-resolution structures of both transporters establish the structural basis for the inhibitor's selectivity to UT-B, and the identification of multiple binding sites for the inhibitor will aid with the development of drug lead molecules targeting both transporters. Our study also discovers phospholipids associating with the urea transporters by combining structural observations, native MS, and lipidomics analysis. These insights improve our understanding of urea transporter function at a molecular level and provide a blueprint for a structure-guided design of therapeutics targeting these transporters.
History
DepositionNov 10, 2022-
Header (metadata) releaseOct 4, 2023-
Map releaseOct 4, 2023-
UpdateOct 11, 2023-
Current statusOct 11, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16110.png

Downloads & links

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Map

FileDownload / File: emd_16110.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.)
0.82 Å/pix.
x 300 pix.
= 246. Å		0.82 Å/pix.
x 300 pix.
= 246. Å		0.82 Å/pix.
x 300 pix.
= 246. Å

Surface

Projections

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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: 0.7
Minimum - Maximum-3.5310364 - 5.175992
Average (Standard dev.)0.0026973225 (±0.15247348)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 246.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_16110_msk_1.map
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Half map: #1

Fileemd_16110_half_map_1.map
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Half map: #2

Fileemd_16110_half_map_2.map
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Sample components

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Entire : Trimer-like complex of Human UT-A

EntireName: Trimer-like complex of Human UT-A
Components
  • Complex: Trimer-like complex of Human UT-A
    • Protein or peptide: Urea transporter 2
  • Ligand: di-heneicosanoyl phosphatidyl choline
  • Ligand: Lauryl Maltose Neopentyl Glycol
  • Ligand: water

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Supramolecule #1: Trimer-like complex of Human UT-A

SupramoleculeName: Trimer-like complex of Human UT-A / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 120 KDa

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Macromolecule #1: Urea transporter 2

MacromoleculeName: Urea transporter 2 / type: protein_or_peptide / ID: 1
Details: This model is based on the N-terminal half of the protein UT-A. However, UT-A consists of two similar domains, and the map is sometimes ambiguous whether the structure is of the N-terminal ...Details: This model is based on the N-terminal half of the protein UT-A. However, UT-A consists of two similar domains, and the map is sometimes ambiguous whether the structure is of the N-terminal or C-terminal half. Much of the map is in line with amino acids from its N-terminal domain.
Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 100.124172 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSDPHSSPLL PEPLSSRYKL YEAEFTSPSW PSTSPDTHPA LPLLEMPEEK DLRSSNEDSH IVKIEKLNER SKRKDDGVAH RDSAGQRCI CLSKAVGYLT GDMKEYRIWL KDKHLALQFI DWVLRGTAQV MFINNPLSGL IIFIGLLIQN PWWTITGGLG T VVSTLTAL ...String:
MSDPHSSPLL PEPLSSRYKL YEAEFTSPSW PSTSPDTHPA LPLLEMPEEK DLRSSNEDSH IVKIEKLNER SKRKDDGVAH RDSAGQRCI CLSKAVGYLT GDMKEYRIWL KDKHLALQFI DWVLRGTAQV MFINNPLSGL IIFIGLLIQN PWWTITGGLG T VVSTLTAL ALGQDRSAIA SGLHGYNGML VGLLMAVFSE KLDYYWWLLF PVTFTAMSCP VLSSALNSIF SKWDLPVFTL PF NIAVTLY LAATGHYNLF FPTTLVEPVS SVPNITWTEM EMPLLLQAIP VGVGQVYGCD NPWTGGVFLV ALFISSPLIC LHA AIGSIV GLLAALSVAT PFETIYTGLW SYNCVLSCIA IGGMFYALTW QTHLLALICA LFCAYMEAAI SNIMSVVGVP PGTW AFCLA TIIFLLLTTN NPAIFRLPLS KVTYPEANRI YYLTVKSGEE EKAPSGGGGE HPPTAGPKVE EGSEAVLSKH RSVFH IEWS SIRRRSKVFG KGEHQERQNK DPFPYRYRKP TVELLDLDTM EESSEIKVET NISKTSWIRS SMAASGKRVS KALSYI TGE MKECGEGLKD KSPVFQFFDW VLRGTSQVMF VNNPLSGILI ILGLFIQNPW WAISGCLGTI MSTLTALILS QDKSAIA AG FHGYNGVLVG LLMAVFSDKG DYYWWLLLPV IIMSMSCPIL SSALGTIFSK WDLPVFTLPF NITVTLYLAA TGHYNLFF P TTLLQPASAM PNITWSEVQV PLLLRAIPVG IGQVYGCDNP WTGGIFLIAL FISSPLICLH AAIGSTMGML AALTIATPF DSIYFGLCGF NSTLACIAIG GMFYVITWQT HLLAIACALF AAYLGAALAN MLSVFGLPPC TWPFCLSALT FLLLTTNNPA IYKLPLSKV TYPEANRIYY LSQEAENLYF Q

UniProtKB: Urea transporter 2

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Macromolecule #2: di-heneicosanoyl phosphatidyl choline

MacromoleculeName: di-heneicosanoyl phosphatidyl choline / type: ligand / ID: 2 / Number of copies: 9 / Formula: PLD
Molecular weightTheoretical: 875.313 Da
Chemical component information

ChemComp-PLD:
di-heneicosanoyl phosphatidyl choline

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Macromolecule #3: Lauryl Maltose Neopentyl Glycol

MacromoleculeName: Lauryl Maltose Neopentyl Glycol / type: ligand / ID: 3 / Number of copies: 15 / Formula: LMN
Molecular weightTheoretical: 1.005188 KDa
Chemical component information

ChemComp-AV0:
Lauryl Maltose Neopentyl Glycol

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Macromolecule #4: water

MacromoleculeName: water / type: ligand / ID: 4 / Number of copies: 18 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / Water

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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

BufferpH: 7.5
Component:
ConcentrationNameFormula
20.0 mMHEPES
150.0 mMSodium ChlorideNaClSodium chloride
0.005 %LMNG
0.0005 %CHS
GridModel: Homemade / Support film - Material: GRAPHENE
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 52.63 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 180448
FSC plot (resolution estimation)

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