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Modelling G protein-coupled receptors
A concrete possibility

STEFANO COSTANZI
National Institute of Diabetes and Digestive and Kidney Diseases, NIH, DHHS. Laboratory of Biological Modeling, 12A South Drive, Rm 4003, MSC 5621,
Bethesda, MD 20892, USA; email: stefanoc@mail.nih.gov

Abstract

G protein-coupled receptors (GPCRs) are alarge superfamily of membrane-bound signalling proteinsthat are involved in the regulation of a wide range ofphysiological functions and constitute the most commontarget for therapeutic intervention. Due to the paucity ofcrystal structures, homology modelling has become awidespread technique for the construction of GPCR models,which have been applied to the study of their structurefunctionrelationships and to the identification of leadligands through virtual screening. Rhodopsin has been foryears the only available template. However, recentbreakthroughs in GPCR crystallography have led to thesolution of the structures of a few additional receptors. Inlight of these newly elucidated crystal structures, we havebeen able to produce a substantial amount of data todemonstrate that accurate models of GPCRs in complexwith their ligands can be constructed through homologymodelling followed by fully flexible molecular docking.These results have been confirmed by our success in the firstblind assessment of GPCR modelling and docking,organized in coordination with the solution of the X-raystructure of the adenosine A2A receptor. Taken together,these data indicate that: a) the transmembrane helicalbundle can be modelled with considerable accuracy; b)predicting the binding mode of a ligand, although doable,is challenging; c) modelling of the extracellular andintracellular loops is still problematic.