Abstract

For many G protein-coupled receptors (GPCRs), ligand-binding sites are deeply embedded within and around the central pocket formed by their seven transmembrane-spanning α-helical domains. Traditionally, these binding sites are thought to be accessible to endogenous ligands from the aqueous phase. Recent advances in structural biology of GPCRs, along with biophysical and computational studies suggest that amphiphilic and lipophilic molecules may gain access to these receptors by first partitioning into the membrane and then reaching via lateral diffusion through the lipid bilayer. In addition, several crystal structures of class A and class B GPCRs bound to their ligands offer unprecedented details on the existence of lipid-facing allosteric binding sites outside the transmembrane helices that can be reached only via lipid pathways. The highly ordered structure of the lipid bilayer may guide lipophilic or amphiphilic drug molecule to a specific depth within the bilayer, affecting its local concentration near the binding site, and influencing its binding kinetics. Additionally, the constraints of the lipid bilayer including its composition and biophysical properties might play a critical role in "pre-organizing" ligand molecules in apposite orientation and conformation to facilitate receptor binding. Despite its conspicuous involvement in molecular recognition processes, the critical role of membrane in ligand-binding mechanism to lipid-exposed transmembrane binding sites remains poorly understood, and warrants comprehensive investigation. The knowledge of mechanistic understanding of structure-membrane interactions relationship of drugs will not only provide useful insights to receptor binding kinetics, but also enhance our ability to take advantage of the apparent membrane contributions in rational design of drugs targeting transmembrane proteins with improved efficacy and safety. In this minireview, we summarize recent structural and computational studies in this direction, elucidating lipid pathways of ligand access and binding mechanisms for several orthosteric and allosteric ligands of class A and class B GPCRs.