RT Journal Article
SR Electronic
T1 What Can Crystal Structures of Aminergic Receptors Tell Us about Designing Subtype-Selective Ligands?
JF Pharmacological Reviews
JO Pharmacol Rev
FD American Society for Pharmacology and Experimental Therapeutics
SP 198
OP 213
DO 10.1124/pr.114.009944
VO 67
IS 1
A1 Mayako Michino
A1 Thijs Beuming
A1 Prashant Donthamsetti
A1 Amy Hauck Newman
A1 Jonathan A. Javitch
A1 Lei Shi
A2 David R. Sibley
YR 2015
UL http://pharmrev.aspetjournals.org/content/67/1/198.abstract
AB G protein–coupled receptors (GPCRs) are integral membrane proteins that represent an important class of drug targets. In particular, aminergic GPCRs interact with a significant portion of drugs currently on the market. However, most drugs that target these receptors are associated with undesirable side effects, which are due in part to promiscuous interactions with close homologs of the intended target receptors. Here, based on a systematic analysis of all 37 of the currently available high-resolution crystal structures of aminergic GPCRs, we review structural elements that contribute to and can be exploited for designing subtype-selective compounds. We describe the roles of secondary binding pockets (SBPs), as well as differences in ligand entry pathways to the orthosteric binding site, in determining selectivity. In addition, using the available crystal structures, we have identified conformational changes in the SBPs that are associated with receptor activation and explore the implications of these changes for the rational development of selective ligands with tailored efficacy.