TY  - JOUR
AU  - Cao, Ruyin
AU  - Rossetti, Giulia
AU  - Bauer, Andreas
AU  - Carloni, Paolo
TI  - Binding of the Antagonist Caffeine to the Human Adenosine Receptor hA2AR in Nearly Physiological Conditions
JO  - PLoS one
VL  - 10
IS  - 5
SN  - 1932-6203
PB  - PLoS
M1  - FZJ-2015-06144
SP  - e0126833
PY  - 2015
AB  - Lipid composition may significantly affect membrane proteins function, yet its impact on the protein structural determinants is not well understood. Here we present a comparative molecular dynamics (MD) study of the human adenosine receptor type 2A (hA(2A)R) in complex with caffeine--a system of high neuro-pharmacological relevance--within different membrane types. These are POPC, mixed POPC/POPE and cholesterol-rich membranes. 0.8-μs MD simulations unambiguously show that the helical folding of the amphipathic helix 8 depends on membrane contents. Most importantly, the distinct cholesterol binding into the cleft between helix 1 and 2 stabilizes a specific caffeine-binding pose against others visited during the simulation. Hence, cholesterol presence (~33%-50% in synaptic membrane in central nervous system), often neglected in X-ray determination of membrane proteins, affects the population of the ligand binding poses. We conclude that including a correct description of neuronal membranes may be very important for computer-aided design of ligands targeting hA(2A)R and possibly other GPCRs.
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000354921400079
C6  - pmid:25992797
DO  - DOI:10.1371/journal.pone.0126833
UR  - https://juser.fz-juelich.de/record/256135
ER  -