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| Home > Publications database > Binding of the Antagonist Caffeine to the Human Adenosine Receptor hA2AR in Nearly Physiological Conditions |
| Home > Publications database > Binding of the Antagonist Caffeine to the Human Adenosine Receptor hA2AR in Nearly Physiological Conditions |
| Journal Article | FZJ-2015-06144 |
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2015
PLoS
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Please use a persistent id in citations: http://hdl.handle.net/2128/9346 doi:10.1371/journal.pone.0126833
Abstract: 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.
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