Abstract
A rich diversity of transmembrane G protein-coupled receptors (GPCRs) are used by eukaryotes to sense physical and chemical signals. In humans alone, 800 GPCRs comprise the largest and most therapeutically targeted receptor class. Recent advances in GPCR structural biology have produced hundreds of GPCR structures solved by X-ray diffraction and increasingly, cryo-electron microscopy (cryo-EM). Many of these structures are stabilized by site-specific cholesterol binding, but it is unclear whether these interactions are a product of recurring cholesterol-binding motifs and if observed patterns of cholesterol binding differ by experimental technique. Here, we comprehensively analyze the location and composition of cholesterol binding sites in the current set of 473 human GPCR structural chains. Our findings establish that cholesterol binds similarly in cryo-EM and X-ray structures and show that 92% of cholesterol molecules on GPCR surfaces reside in predictable locations that lack discernable cholesterol-binding motifs.
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•A rapidly growing number of GPCR structures have been solved by cryo-EM•Cholesterol-binding patterns are similar in cryo-EM and X-ray GPCR structures•92% of cholesterol in GPCR structures map to 12 Cholesterol Network Clusters (CNCs)•There are no broadly recurring cholesterol-binding motifs in GPCRs
Cholesterol (CLR) regulates G protein-coupled receptor (GPCR) function, but it is unclear if this is due to binding conserved CLR motifs. Taghon et al. collect, validate, and cluster all GPCR-bound CLR in the PDB and show that 92% reside in 12 distinct GPCR regions that lack consensus CLR-binding sites.
