期刊
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
卷 11, 期 9, 页码 4439-4449出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jctc.5b00472
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资金
- Julich-Aachen Research Alliance [JARA0082, JARA0023]
- Programma Operativo del Fondo Sociale Europeo of Regione Autonoma Friuli Venezia Giulia
- CIRMMP (Consorzio Interuniversitario di Risonanze Magnetiche di Metallo-Proteine)
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/dass 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 complet with its agonist strychnine. Three similar to 1 mu s 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.
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