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Cholesterol Binds G Protein‐coupled Receptors in Conserved Sites Without Recurring Motifs
Author(s) -
Taghon Geoffrey,
Rowe Jacob,
Kapolka Nicholas,
Isom Daniel
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03682
Subject(s) - g protein coupled receptor , allosteric regulation , biology , binding site , computational biology , receptor , structural motif , transmembrane domain , biochemistry , chemistry
Human G protein‐coupled receptors (GPCRs) are an 800‐member transmembrane receptor superfamily with huge pharmacological utility. Resolution breakthroughs in cryoelectron microscopy (cryo‐EM) and continued evolution of x‐ray crystallography have led to many GPCR structures with resolved bound lipids, especially the known GPCR stabilizer cholesterol. Cholesterol‐GPCR binding is a well‐studied allosteric regulator shared by many receptors and conserved binding sites could be a valuable pharmacological target. We examined the importance of specific sequence motifs, attempted to calculate a consensus motif, and compared the total evidence from both cryo‐EM and x‐ray structures. We analyze the current scope of cholesterol‐GPCR binding interactions in Protein Data Bank structures, and find that 92% of cholesterol associates with GPCRs in 12 distinct sites on the transmembrane bundle, surprisingly without consensus binding residues. Additionally, we find that previously reported cholesterol‐GPCR binding motifs are not generalizable, and a new consensus could not be found via residue alignment. The same cholesterol binding patterns hold for a comprehensive dataset including x‐ray and cryo‐EM structures, indicating that in most cases GPCR side chain environment has little impact.