The activation mechanisms of G protein-coupled receptors : the case of the adenosine A2B and HCA2/3 receptors

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The activation mechanisms of G protein-coupled receptors : the case of the adenosine A2B and HCA2/3 receptors

Type: Doctoral Thesis
Title: The activation mechanisms of G protein-coupled receptors : the case of the adenosine A2B and HCA2/3 receptors
Author: Liu, R.
Issue Date: 2016-12-08
Keywords: GPCRs/G protein
Saccharomyces cerevisiae
A2B eceptor
Hydroxycarboxylic acid receptors
Abstract: Identifying and elucidating the functions and activation of GPCRs will provide opportunities for novel drug discovery. We confirmed that a yeast system with an extended library of G proteins is very well suited for the study of GPCR activation, G protein coupling profiles, receptor-G protein binding and G protein selectivity. For example, we used a scanning mutagenesis approach of the NPxxY(x)5,6F motif and of helix 8 of the adenosine A2B receptor (A2BR), and learned among others that amino acid residues in these motifs are crucial for receptor function, since alanine mutants of these amino acid residues led to a complete loss of function. Hopefully, such findings can contribute to further drug development. We also focused on structure-kinetics relationship (SKR) studies next to the more traditional Structure-affinity relationship (SAR) studies. We found two compounds showing longer residence times than nicotinic acid, which may provide clues for further drug discovery efforts on this receptor. All in all, the variety of methods described in this thesis provided us a detailed understanding of receptor function, suggesting that novel avenues for further drug discovery on these established targets is entirely feasible.
Promotor: Supervisor: A.P. IJzerman
Faculty: Science
University: Leiden
Handle: http://hdl.handle.net/1887/44797
 

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application/pdf Curriculum Vitae_List of publications 295.6Kb View/Open
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