title: The approach of conformational chimeras to model the role of proline-containing helices on GPCR mobility: the fertile case of Cys-LTR1.
abstract: The homology modeling of GPCRs has benefitted vastly from the availability of some resolved structures, which allow the generation of many reliable GPCR models. However, the dynamic behavior of such receptors has been only minimally examined in silico, although several pieces of evidence have highlighted some conformational switches that can orchestrate the activation mechanism. Among such switches, Pro-containing helices play a key role in determining bending in TM helices and thereby the width of the TM bundle. The approach proposed herein involves the generation of a set of possible models (conformational chimeras) by exhaustively combining the two main conformations (straight and bent) that a Pro-containing helix can assume. This approach was validated by generating conformational chimeras for the Cys-LTR1 receptor, which is involved in contractile and inflammatory processes. The generated chimeras were then used for docking a small set of representative ligands. The results revealed the flexibility mechanisms of Cys-LTR1, showing how the docked agonists vary their stabilizing interactions, shifting from the open to closed state, and how the examined antagonists are able to block the receptor in an open and inactive conformation, thus behaving as inverse agonists. This study emphasizes the promising potential of chimera modeling, confirms the key role of proline residues in receptor activation, and suggests that docking results can be improved by considering the often-overlooked flexibility of receptors.
authors.affiliation: Recordati S.p.A. Drug Discovery, via Civitali 1, 20148 Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bettinelli
authors.forename: Davide
authors.initials: D
authors.lastname: Graziani
authors.forename: Cristina
authors.initials: C
authors.lastname: Marconi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pedretti
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
mesh_terms: D001665:Binding Sites; D006801:Humans; D020024:Leukotriene Antagonists / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D011392:Proline / Q000737:chemistry; D017433:Protein Structure, Secondary; D018077:Receptors, Leukotriene / Q000737:chemistry* / Q000378:metabolism
chemical_list: D020024:Leukotriene Antagonists; D018077:Receptors, Leukotriene; D011392:Proline; C083169:leukotriene D4 receptor