SLC22 transporters involved in drug elimination and organ distribution are polyspecific. Now, the first cryo-EM structure of SLC22A3 (OCT3) is available from the Sitte and Korkhov groups. It paves the way for better understanding OCT3 function and for revealing the exact mechanisms conferring polyspecificity of the whole SLC22 family.
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Targeted mutagenesis of negatively charged amino acids outlining the substrate translocation path within the human organic cation transporter 3.
Biochem Pharmacol
May 2024
Institute of Clinical Pharmacology, University Medical Center Göttingen, D-37075 Göttingen, Germany.
Recently published cryo-EM structures of human organic cation transporters of the SLC22 family revealed seven, sequentially arranged glutamic and aspartic acid residues, which may be relevant for interactions with positively charged substrates. We analyzed the functional consequences of removing those negative charges by creating D155N, E232Q, D382N, E390Q, E451Q, E459Q, and D478N mutants of OCT3. E232Q, E459Q, and D478N resulted in a lack of localization in the outer cell membrane and no relevant uptake activity.
View Article and Find Full Text PDFOCTN1 (SLC22A4) displays two different transport pathways for organic cations or zwitterions.
Biochim Biophys Acta Biomembr
February 2024
Department DiBEST (Biologia, Ecologia, Scienze della Terra) Laboratory of Biochemistry, Molecular Biotechnology, and Molecular Biology, University of Calabria, Via Bucci 4C, 6C, 87036 Arcavacata di Rende, Italy; National Research Council (CNR), Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), via Amendola 122/O, 70126 Bari, Italy. Electronic address:
Background: OCTN1 belongs to the SLC22 family, which includes transporters for cationic, zwitterionic, and anionic substrates. OCTN1 function and role in cells are still poorly understood. Not only cations, such as TEA, but also zwitterions, such as carnitine and ergothioneine, figure among transported molecules.
View Article and Find Full Text PDFStereoselectivity in Cell Uptake by SLC22 Organic Cation Transporters 1, 2, and 3.
J Med Chem
December 2023
Institute of Clinical Pharmacology, University Medical Center Göttingen, Göttingen D-37075, Germany.
Stereoselectivity can be most relevant in drug metabolism and receptor binding. Although drug membrane transport might be equally important for small-molecule pharmacokinetics, the extent of stereoselectivity in membrane transport is largely unknown. Here, we characterized the stereoselective transport of 18 substrates of SLC22 organic cation transporters (OCTs) 1, 2, and 3.
View Article and Find Full Text PDFThe substrate and inhibitor binding mechanism of polyspecific transporter OAT1 revealed by high-resolution cryo-EM.
Nat Struct Mol Biol
November 2023
Laboratory of Membrane Proteins and Structural Biology, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
Organic anion transporters (OATs) of the SLC22 family have crucial roles in the transport of organic anions, including metabolites and therapeutic drugs, and in transporter-mediated drug-drug interactions. In the kidneys, OATs facilitate the elimination of metabolic waste products and xenobiotics. However, their transport activities can lead to the accumulation of certain toxic compounds within cells, causing kidney damage.
View Article and Find Full Text PDFThe end of the beginning in understanding SLC22 polyspecificity.
Trends Pharmacol Sci
July 2023
Department of General Pharmacology, Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany. Electronic address:
SLC22 transporters involved in drug elimination and organ distribution are polyspecific. Now, the first cryo-EM structure of SLC22A3 (OCT3) is available from the Sitte and Korkhov groups. It paves the way for better understanding OCT3 function and for revealing the exact mechanisms conferring polyspecificity of the whole SLC22 family.
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