Structural Aspects of Photopharmacology: Insight into the Binding of Photoswitchable and Photocaged Inhibitors to the Glutamate Transporter Homologue

J Am Chem Soc. 2021 Jan 27;143(3):1513-1520. doi: 10.1021/jacs.0c11336. Epub 2021 Jan 15.

Abstract

Photopharmacology addresses the challenge of drug selectivity and side effects through creation of photoresponsive molecules activated with light with high spatiotemporal precision. This is achieved through incorporation of molecular photoswitches and photocages into the pharmacophore. However, the structural basis for the light-induced modulation of inhibitory potency in general is still missing, which poses a major design challenge for this emerging field of research. Here we solved crystal structures of the glutamate transporter homologue GltTk in complex with photoresponsive transport inhibitors-azobenzene derivative of TBOA (both in trans and cis configuration) and with the photocaged compound ONB-hydroxyaspartate. The essential role of glutamate transporters in the functioning of the central nervous system renders them potential therapeutic targets in the treatment of neurodegenerative diseases. The obtained structures provide a clear structural insight into the origins of photocontrol in photopharmacology and lay the foundation for application of photocontrolled ligands to study the transporter dynamics by using time-resolved X-ray crystallography.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System X-AG / antagonists & inhibitors*
  • Amino Acid Transport System X-AG / chemistry
  • Amino Acid Transport System X-AG / metabolism*
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / metabolism*
  • Aspartic Acid / radiation effects
  • Azo Compounds / chemistry
  • Azo Compounds / metabolism*
  • Azo Compounds / radiation effects
  • Crystallography, X-Ray
  • Protein Binding
  • Stereoisomerism
  • Thermococcus / chemistry
  • Ultraviolet Rays

Substances

  • Amino Acid Transport System X-AG
  • Azo Compounds
  • Aspartic Acid