TY  - JOUR
AU  - Arkhipova, Valentina
AU  - Fu, Haigen
AU  - Hoorens, Mark W. H.
AU  - Trinco, Gianluca
AU  - Lameijer, Lucien N.
AU  - Marin, Egor
AU  - Feringa, Ben L.
AU  - Poelarends, Gerrit J.
AU  - Szymanski, Wiktor
AU  - Slotboom, Dirk J.
AU  - Guskov, Albert
TI  - Structural Aspects of Photopharmacology: Insight into the Binding of Photoswitchable and Photocaged Inhibitors to the Glutamate Transporter Homologue
JO  - Journal of the American Chemical Society
VL  - 143
IS  - 3
SN  - 0002-7863
CY  - Washington, DC
PB  - American Chemical Society
M1  - PUBDB-2021-05024
SP  - 1513 -1520
PY  - 2021
AB  - 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 Glt<sub>Tk</sub> 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:33449695
UR  - <Go to ISI:>//WOS:000614064400032
DO  - DOI:10.1021/jacs.0c11336
UR  - https://bib-pubdb1.desy.de/record/472355
ER  -