TY - JOUR
T1 - Molecular basis of ligand dissociation from the adenosine A2A receptor
AU - Guo, Dong
AU - Pan, Albert C.
AU - Dror, Ron O.
AU - Mocking, Tamara
AU - Liu, Rongfang
AU - Heitman, Laura H.
AU - Shaw, David E.
AU - IJzerman, Adriaan P.
PY - 2016/5/1
Y1 - 2016/5/1
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.
AB - 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.
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U2 - 10.1124/mol.115.102657
DO - 10.1124/mol.115.102657
M3 - Article
C2 - 26873858
AN - SCOPUS:84963812010
SN - 0026-895X
VL - 89
SP - 485
EP - 491
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 5
ER -