TY - JOUR T1 - Molecular Basis of Ligand Dissociation from the Adenosine A<sub>2A</sub> Receptor JF - Molecular Pharmacology JO - Mol Pharmacol SP - 485 LP - 491 DO - 10.1124/mol.115.102657 VL - 89 IS - 5 AU - Dong Guo AU - Albert C. Pan AU - Ron O. Dror AU - Tamara Mocking AU - Rongfang Liu AU - Laura H. Heitman AU - David E. Shaw AU - Adriaan P. IJzerman Y1 - 2016/05/01 UR - http://molpharm.aspetjournals.org/content/89/5/485.abstract N2 - How drugs dissociate from their targets is largely unknown. We investigated the molecular basis of this process in the adenosine A2A receptor (A2AR), 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 A2AR. 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. ER -