Predicting GPCR promiscuity using binding site features

Anat Levit, Thijs Beuming, Goran Krilov, Woody Sherman, Masha Y. Niv*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


G protein-coupled receptors (GPCRs) represent a large family of signaling proteins that includes many therapeutic targets. GPCR ligands include odorants, tastants, and neurotransmitters and vary in size and properties. Dramatic chemical diversity may occur even among ligands of the same receptor. Our goal is to unravel the structural and chemical features that determine GPCRs' promiscuity toward their ligands. We perform statistical analysis using more than 30 descriptors related to the sequence, physicochemical, structural, and energetic properties of the GPCR binding sites - we find that the chemical variability of antagonists significantly correlates with the binding site hydrophobicity and anticorrelates with the number of hydrogen bond donors in the binding site. The number of disulfide bridges in the extracellular region of a receptor anticorrelates with the range of molecular weights of its antagonists, highlighting the role of the entrance pathway in determining the size selectivity for GPCR antagonists. The predictive capability of the model is successfully validated using a separate set of GPCRs, using either X-ray structures or homology models.

Original languageAmerican English
Pages (from-to)184-194
Number of pages11
JournalJournal of Chemical Information and Modeling
Issue number1
StatePublished - 27 Jan 2014


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