Abstract:
:Ion channels and G protein-coupled receptors (GPCRs) are regulated by lipids in their membrane environment. Structural studies combined with biophysical and molecular simulation investigations reveal interaction sites for specific lipids on membrane protein structures. For K channels, PIP2 plays a key role in regulating Kv and Kir channels. Likewise, several recent cryo-EM structures of TRP channels have revealed bound lipids, including PIP2 and cholesterol. Among the pentameric ligand-gated ion channel family, structural and biophysical studies suggest the M4 TM helix may act as a lipid sensor, e.g., forming part of the binding sites for neurosteroids on the GABAA receptor. Structures of GPCRs have revealed multiple cholesterol sites, which may modulate both receptor dynamics and receptor oligomerization. PIP2 also interacts with GPCRs and may modulate their interactions with G proteins. Overall, it is evident that multiple lipid binding sites exist on channels and receptors that modulate their function allosterically and are potential druggable sites.
journal_name
Annu Rev Pharmacol Toxicoljournal_title
Annual review of pharmacology and toxicologyauthors
Duncan AL,Song W,Sansom MSPdoi
10.1146/annurev-pharmtox-010919-023411subject
Has Abstractpub_date
2020-01-06 00:00:00pages
31-50eissn
0362-1642issn
1545-4304journal_volume
60pub_type
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