Journal
MOLECULAR PHARMACOLOGY
Volume 89, Issue 5, Pages 485-491Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.115.102657
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- Innovational Research Incentive Scheme of The Netherlands Research Organization [11188]
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How drugs dissociate from their targets is largely unknown. We investigated the molecular basis of this process in the adenosine A(2A) receptor (A(2A)R), a prototypical G protein-coupled receptor (GPCR). Through kinetic radioligand binding experiments, we characterized mutant receptors selected based on molecular dynamic simulations of the antagonist ZM241385 dissociating from the A(2A)R. We discovered mutations that dramatically altered the ligand's dissociation rate despite only marginally influencing its binding affinity, demonstrating that even receptor features with little contribution to affinity may prove critical to the dissociation process. Our results also suggest that ZM241385 follows a multistep dissociation pathway, consecutively interacting with distinct receptor regions, a mechanism that may also be common to many other GPCRs.
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