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- PDB-8blo: Human Urea Transporter UT-A (N-Terminal Domain Model) -

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Basic information

Entry
Database: PDB / ID: 8blo
TitleHuman Urea Transporter UT-A (N-Terminal Domain Model)
ComponentsUrea transporter 2
KeywordsTRANSPORT PROTEIN / SLC14A2 / UT2 / UT-A / Urea Transporter / Inhibitor / Solute Carrier
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
di-heneicosanoyl phosphatidyl choline / Urea transporter 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsChi, G. / Pike, A.C.W. / Maclean, E.M. / Mukhopadhyay, S.M.M. / Bohstedt, T. / Scacioc, A. / Wang, D. / McKinley, G. / Fernandez-Cid, A. / Arrowsmith, C.H. ...Chi, G. / Pike, A.C.W. / Maclean, E.M. / Mukhopadhyay, S.M.M. / Bohstedt, T. / Scacioc, A. / Wang, D. / McKinley, G. / Fernandez-Cid, A. / Arrowsmith, C.H. / Bountra, C. / Edwards, A. / Burgess-Brown, N.A. / van Putte, W. / Duerr, K.
Funding support United Kingdom, European Union, 2items
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, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 4, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Database references / Source and taxonomy
Category: citation / citation_author ...citation / citation_author / em_entity_assembly_naturalsource / em_entity_assembly_recombinant / entity_src_gen
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name / _em_entity_assembly_naturalsource.id / _em_entity_assembly_recombinant.id / _entity_src_gen.host_org_common_name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)323,32827
Polymers300,3733
Non-polymers22,95624
Water32418
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area15750 Å2
ΔGint-89 kcal/mol
Surface area38780 Å2
MethodPISA

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Components

#1: Protein Urea transporter 2 / Solute carrier family 14 member 2 / Urea transporter / kidney


Mass: 100124.172 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
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.
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC14A2, HUT2, UT2 / Production host: Homo sapiens (human) / References: UniProt: Q15849
#2: Chemical
ChemComp-PLD / di-heneicosanoyl phosphatidyl choline


Mass: 875.313 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C50H101NO8P
#3: Chemical
ChemComp-LMN / Lauryl Maltose Neopentyl Glycol / 2,2-didecylpropane-1,3-bis-b-D-maltopyranoside


Mass: 1005.188 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: C47H88O22 / Comment: detergent*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 18 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: Trimer-like complex of Human UT-A / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.12 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPES1
2150 mMSodium ChlorideNaCl1
30.005 %LMNG1
40.0005 %CHS1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Homemade
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2800 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 52.63 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM softwareName: cryoSPARC / Category: 3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C3 (3 fold cyclic)
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 180448 / Symmetry type: POINT

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