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- EMDB-16112: Human Urea Transporter UT-B/UT1 in Complex with Inhibitor UTBinh-14 -

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Basic information

Entry
Database: EMDB / ID: EMD-16112
TitleHuman Urea Transporter UT-B/UT1 in Complex with Inhibitor UTBinh-14
Map data
Sample
  • Complex: Homotrimeric complex of Human Urea Transporter UT-B
    • Protein or peptide: Urea transporter 1
  • Ligand: PHOSPHATIDYLETHANOLAMINE
  • Ligand: DODECYL-BETA-D-MALTOSIDE
  • Ligand: 10-(4-ethylphenyl)sulfonyl-~{N}-(thiophen-2-ylmethyl)-5-thia-1,8,11,12-tetrazatricyclo[7.3.0.0^{2,6}]dodeca-2(6),3,7,9,11-pentaen-7-amine
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: water
KeywordsSLC14A1 / UT1 / UT-B / Urea Transporter / Inhibitor / Solute Carrier / TRANSPORT PROTEIN
Function / homology
Function and homology information


urea channel activity / urea transport / Transport of bile salts and organic acids, metal ions and amine compounds / urea transmembrane transporter activity / urea transmembrane transport / water transmembrane transporter activity / establishment of localization in cell / transmembrane transport / basolateral plasma 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: 2.6 Å
AuthorsChi G / Dietz L / Pike ACW / Maclean EM / Mukhopadhyay SMM / Bohstedt T / Wang D / Scacioc A / McKinley G / Arrowsmith CH ...Chi G / Dietz L / Pike ACW / Maclean EM / Mukhopadhyay SMM / Bohstedt T / Wang D / Scacioc A / McKinley G / Arrowsmith CH / Edwards A / Bountra C / Fernandez-Cid A / Burgess-Brown NA / Duerr KL
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Wellcome Trust106169/Z//14/Z United Kingdom
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_16112.png

Downloads & links

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Map

FileDownload / File: emd_16112.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

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.9
Minimum - Maximum-3.235934 - 4.45492
Average (Standard dev.)0.0041663805 (±0.11867414)
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_16112_msk_1.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_16112_half_map_1.map
Projections & Slices
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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_16112_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Homotrimeric complex of Human Urea Transporter UT-B

EntireName: Homotrimeric complex of Human Urea Transporter UT-B
Components
  • Complex: Homotrimeric complex of Human Urea Transporter UT-B
    • Protein or peptide: Urea transporter 1
  • Ligand: PHOSPHATIDYLETHANOLAMINE
  • Ligand: DODECYL-BETA-D-MALTOSIDE
  • Ligand: 10-(4-ethylphenyl)sulfonyl-~{N}-(thiophen-2-ylmethyl)-5-thia-1,8,11,12-tetrazatricyclo[7.3.0.0^{2,6}]dodeca-2(6),3,7,9,11-pentaen-7-amine
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: water

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Supramolecule #1: Homotrimeric complex of Human Urea Transporter UT-B

SupramoleculeName: Homotrimeric complex of Human Urea Transporter UT-B / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Urea transporter 1

MacromoleculeName: Urea transporter 1 / type: protein_or_peptide / ID: 1
Details: N211A is an engineered mutation. The rest are natural variants.
Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.17741 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MFPKALGYVT GDMKELANQL KDKPVVLQFI DWILRGISQV VFVNNPVSGI LILVGLLVQN PWWALTGWLG TVVSTLMALL LSQDRSLIA SGLYGYNATL VGVLMAVFSD KGDYFWWLLL PVCAMSMTCP IFSSALNSVL SKWDLPVFTL PFNMALSMYL S ATGHYNPF ...String:
MFPKALGYVT GDMKELANQL KDKPVVLQFI DWILRGISQV VFVNNPVSGI LILVGLLVQN PWWALTGWLG TVVSTLMALL LSQDRSLIA SGLYGYNATL VGVLMAVFSD KGDYFWWLLL PVCAMSMTCP IFSSALNSVL SKWDLPVFTL PFNMALSMYL S ATGHYNPF FPAKLVIPIT TAPQISWSDL SALELLKSIP VGVGQIYGCD NPWTGGIFLG AILLSSPLMC LHAAIGSLLG IA AGLSLSA PFENIYFGLW GFNSSLACIA MGGMFMALTW QTHLLALGCA LFTAYLGVGM ANFMAEVGLP ACTWPFCLAT LLF LIMTTK NSNIYKMPLS KVTYPEENRI FYLQAKKRMV ESPLAENLYF Q

UniProtKB: Urea transporter 1

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Macromolecule #2: PHOSPHATIDYLETHANOLAMINE

MacromoleculeName: PHOSPHATIDYLETHANOLAMINE / type: ligand / ID: 2 / Number of copies: 6 / Formula: PTY
Molecular weightTheoretical: 734.039 Da
Chemical component information

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM / Phosphatidylethanolamine

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Macromolecule #3: DODECYL-BETA-D-MALTOSIDE

MacromoleculeName: DODECYL-BETA-D-MALTOSIDE / type: ligand / ID: 3 / Number of copies: 51 / Formula: LMT
Molecular weightTheoretical: 510.615 Da
Chemical component information

ChemComp-LMT:
DODECYL-BETA-D-MALTOSIDE / detergent*YM

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Macromolecule #4: 10-(4-ethylphenyl)sulfonyl-~{N}-(thiophen-2-ylmethyl)-5-thia-1,8,...

MacromoleculeName: 10-(4-ethylphenyl)sulfonyl-~{N}-(thiophen-2-ylmethyl)-5-thia-1,8,11,12-tetrazatricyclo[7.3.0.0^{2,6}]dodeca-2(6),3,7,9,11-pentaen-7-amine
type: ligand / ID: 4 / Number of copies: 6 / Formula: 5D3
Molecular weightTheoretical: 455.576 Da
Chemical component information

ChemComp-5D3:
10-(4-ethylphenyl)sulfonyl-~{N}-(thiophen-2-ylmethyl)-5-thia-1,8,11,12-tetrazatricyclo[7.3.0.0^{2,6}]dodeca-2(6),3,7,9,11-pentaen-7-amine

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Macromolecule #5: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 5 / Number of copies: 3 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 66 / 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

Concentration3 mg/mL
BufferpH: 7.5
Component:
ConcentrationNameFormula
20.0 mMHEPES
150.0 mMSodium ChlorideNaClSodium chloride
0.02 %DDM
0.002 %CHS
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: 2.6 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Number real images: 8221 / Average electron dose: 39.58 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2288882
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: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 258739
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-8blp:
Human Urea Transporter UT-B/UT1 in Complex with Inhibitor UTBinh-14

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