Transient kinetics reveal the mechanism of competitive inhibition of the neutral amino acid transporter ASCT2.

ABSTRACT: ASCT2 (alanine serine cysteine transporter 2), a member of the solute carrier 1 family, mediates Na⁺-dependent exchange of small neutral amino acids across cell membranes. ASCT2 was shown to be highly expressed in tumor cells, making it a promising target for anticancer therapies. In this study, we explored the binding mechanism of the high-affinity competitive inhibitor L-cis hydroxyproline biphenyl ester (Lc-BPE) with ASCT2, using electrophysiological and rapid kinetic methods. Our investigations reveal that Lc-BPE binding requires one or two Na⁺ ions initially bound to the apo-transporter with high affinity, with Na1 site occupancy being more critical for inhibitor binding. In contrast to the amino acid substrate bound form, the final, third Na⁺ ion cann

SUBMITTER: Dong Y 

PROVIDER: S-EPMC11193019 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature