Molecular Basis of Ligand Dissociation from the Adenosine A(2A) Receptor

Guo, D.; Pan, A.C.; Dror, R.O.; Mocking, T.; Liu, R.; Heitman, L.H.; ... ; IJzerman, A.P. (2016)

Article / Letter to editor

Molecular Basis of Ligand Dissociation from the Adenosine A_2A Receptor

Dong Guo, Albert C. Pan, Ron O. Dror, Tamara Mocking, Rongfang Liu, Laura H. Heitman, David E. Shaw and Adriaan P. IJzerman

Molecular Pharmacology May 2016, 89 (5) 485-491; DOI: https://doi.org/10.1124/mol.115.102657

Abstract

How drugs dissociate from their targets is largely unknown. We investigated the molecular basis of this process in the adenosine A_2A receptor (A_2AR), 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_2AR. 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.

• All authors: Guo, D.; Pan, A.C.; Dror, R.O.; Mocking, T.; Liu, R.; Heitman, L.H.; Shaw, D.E.; IJzerman, A.P.
• Date: 2016-05-31
• Volume: 89
• Issue: 5
• Pages: 485 - 491
• DOI: doi:10.1124/mol.115.102657