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TitleStructural characterization of human urea transporters UT-A and UT-B and their inhibition.
Journal, issue, pagesSci Adv, Vol. 9, Issue 39, Page eadg8229, Year 2023
Publish dateSep 29, 2023
AuthorsGamma 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 /
PubMed AbstractIn 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.
External linksSci Adv / PubMed:37774028 / PubMed Central
MethodsEM (single particle)
Resolution2.6 - 3.0 Å
Structure data

16110

8blo

EMDB-16110, PDB-8blo:
Human Urea Transporter UT-A (N-Terminal Domain Model)
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-16111: Map of Human Urea Transporter UT-A Collected with 0 and 30 Degree Tilts
Method: EM (single particle) / Resolution: 3.0 Å

16112

8blp

EMDB-16112, PDB-8blp:
Human Urea Transporter UT-B/UT1 in Complex with Inhibitor UTBinh-14
Method: EM (single particle) / Resolution: 2.6 Å

Chemicals

ChemComp-PLD:
di-heneicosanoyl phosphatidyl choline

ChemComp-LMN:
Lauryl Maltose Neopentyl Glycol / detergent*YM

ChemComp-HOH:
WATER / Water

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM / Phosphatidylethanolamine

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

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

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / SLC14A2 / UT2 / UT-A / Urea Transporter / Inhibitor / Solute Carrier / SLC14A1 / UT1 / UT-B

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