TY  - JOUR
AU  - Sandal, Massimo
AU  - Behrens, Maik
AU  - Brockhoff, Anne
AU  - Musiani, Francesco
AU  - Giorgetti, Alejandro
AU  - Carloni, Paolo
AU  - Meyerhof, Wolfgang
TI  - Evidence for a Transient Additional Ligand Binding Site in the TAS2R46 Bitter Taste Receptor
JO  - Journal of chemical theory and computation
VL  - 11
IS  - 9
SN  - 1549-9626
CY  - Washington, DC
PB  - American Chemical Society (ACS)
M1  - FZJ-2015-05586
SP  - 4439 - 4449
PY  - 2015
AB  - Most human G protein coupled receptors (GPCRs) are activated by small molecules binding to their 7-transmembrane (7-TM) helix bundle. They belong to basally diverging branches: the 25 bitter taste 2 receptors and most members of the very large rhodopsin-like/class A GPCRs subfamily. Some members of the class A branch have been suggested to feature not only an orthosteric agonist-binding site but also a more extracellular or “vestibular” site, involved in the binding process. Here we use a hybrid molecular mechanics/coarse-grained (MM/CG) molecular dynamics approach on a widely studied bitter taste receptor (TAS2R46) receptor in complex with its agonist strychnine. Three ∼1 μs molecular simulation trajectories find two sites hosting the agonist, which together elucidate experimental data measured previously and in this work. This mechanism shares similarities with the one suggested for the evolutionarily distant class A GPCRs. It might be instrumental for the remarkably broad but specific spectrum of agonists of these chemosensory receptors.
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000361087600046
C6  - pmid:26575934
DO  - DOI:10.1021/acs.jctc.5b00472
UR  - https://juser.fz-juelich.de/record/205116
ER  -