Related Experiment Video

Updated: May 28, 2025

A Flow Cytometry-Based Cell Surface Protein Binding Assay for Assessing Selectivity and Specificity of an Anticancer Aptamer
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A Flow Cytometry-Based Cell Surface Protein Binding Assay for Assessing Selectivity and Specificity of an Anticancer Aptamer

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Structural basis of anticancer drug recognition and amino acid transport by LAT1

Yongchan Lee1,2, Chunhuan Jin3, Ryuichi Ohgaki3,4

  • 1Department of Structural Biology, Max Planck Institute of Biophysics, 60438, Frankfurt, Germany. yongchan.lee@biophys.mpg.de.

Nature Communications
|February 14, 2025
PubMed

Insights

Structural insights reveal how LAT1 (SLC7A5) transports amino acids and is inhibited by drugs like JPH203. Understanding these mechanisms is key for cancer therapy and drug delivery advancements.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Transport

Background:

  • The amino acid transporter LAT1 (SLC7A5) is crucial for cancer cell growth, immune responses, and drug delivery.
  • Understanding LAT1's substrate discrimination and inhibition mechanisms is vital, especially for clinically relevant drugs.

Purpose of the Study:

  • To elucidate the structural mechanisms underlying LAT1 substrate transport and inhibition.
  • To provide a molecular basis for how LAT1 recognizes physiological substrates and therapeutic inhibitors.

Main Methods:

  • Determination of six crystal structures of LAT1 in three distinct conformations bound to various ligands.
  • Analysis of ligand-induced conformational changes and their impact on transporter function.

Main Results:

  • The anticancer drug JPH203 traps LAT1 in an outward-facing U-shaped conformation, distinct from substrate-bound states.
  • Physiological substrates like ʟ-Phe do not induce these specific conformational changes, while melphalan inhibits via steric hindrance.
  • The inhibitor BCH induces an occluded state, confirming its substrate-like interaction with LAT1.

Conclusions:

  • These structures provide unprecedented insight into LAT1's substrate recognition and inhibition mechanisms.
  • The findings offer a structural foundation for designing novel LAT1-targeting drugs for cancer therapy and improved drug delivery.

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