Cholesterol footprint in high-resolution structures of serotonin receptors: Where are we now and what does it mean?

An emerging feature of several high-resolution GPCR structures is the presence of closely bound cholesterol molecules. In this Perspective, we share the excitement of the recent advancements in GPCR structural biology. We further highlight our laboratory's journey in comprehensively elucidating functional sensitivity of GPCRs (using the serotonin _1A receptor as a representative neurotransmitter GPCR) to membrane cholesterol and validation using a variety of assays and molecular dynamics simulations. Although high-resolution structures of many GPCRs have been reported in the last few years, the structure of the serotoin _1A receptor proved to be elusive for a long time. Very recently the cryo-EM structure of the serotoin _1A receptor displaying 10 bound cholesterol molecules has been reported. We conclude by providing a critical analysis of caveats involved in GPCR structure determination.
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