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Differences between G‐Protein‐Stabilized Agonist–GPCR Complexes and their Nanobody‐Stabilized Equivalents
Author(s) -
Saleh Noureldin,
Ibrahim Passainte,
Clark Timothy
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201702468
Subject(s) - g protein coupled receptor , metadynamics , agonist , ternary complex , chemistry , receptor , ternary operation , g protein , biophysics , inverse agonist , ligand (biochemistry) , biochemistry , molecular dynamics , biology , enzyme , computational chemistry , computer science , programming language
Protein nanobodies have been used successfully as surrogates for unstable G‐proteins in order to crystallize G‐protein‐coupled receptors (GPCRs) in their active states. We used molecular dynamics (MD) simulations, including metadynamics enhanced sampling, to investigate the similarities and differences between GPCR–agonist ternary complexes with the α‐subunits of the appropriate G‐proteins and those with the protein nanobodies (intracellular binding partners, IBPs) used for crystallization. In two of the three receptors considered, the agonist‐binding mode differs significantly between the two alternative ternary complexes. The ternary‐complex model of GPCR activation entails enhancement of ligand binding by bound IBPs: Our results show that IBP‐specific changes can alter the agonist binding modes and thus also the criteria for designing GPCR agonists.