Aminergic GPCR–Ligand Interactions: A Chemical and Structural Map of Receptor Mutation Data

The
aminergic family of G protein-coupled receptors (GPCRs) plays
an important role in various diseases and represents a major drug
discovery target class. Structure determination of all major aminergic
subfamilies has enabled structure-based ligand design for these receptors.
Site-directed mutagenesis data provides an invaluable complementary
source of information for elucidating the structural determinants
of binding of different ligand chemotypes. The current study provides
a comparative analysis of 6692 mutation data points on 34 aminergic
GPCR subtypes, covering the chemical space of 540 unique ligands from
mutagenesis experiments and information from experimentally determined
structures of 52 distinct aminergic receptor–ligand complexes.
The integrated analysis enables detailed investigation of structural
receptor–ligand interactions and assessment of the transferability
of combined binding mode and mutation data across ligand chemotypes
and receptor subtypes. An overview is provided of the possibilities
and limitations of using mutation data to guide the design of novel
aminergic receptor ligands.