G protein-coupled receptors (GPCRs) are membrane proteins of high pharmaceutical interest. Despite the large size of the superfamily – the human genomes contains genes for about 1,000 GPCRs – experimental crystal structures have only been elucidated for of about 40 different receptors. As a result, the homology modeling technique is commonly applied to extend the available structural knowledge to the receptors for which structures have not been solved. Through this work, using the beta2-adrenergic receptor as a case study, we systematically probed the impact of the use of agonist-bound and blocker-bound structures on the accuracy of the models. In particular, we built models of the receptor based on templates for which structures were solved in complex with both agonists and blockers. Subsequently, we compared the resulting models with structures of the beta2-receptor solved in the activated and in the inactive state to reveal whether or not agonist-bound templates are always preferable to build models reflecting the activated state of the receptor and, vice versa, blocker-bound templates are always preferable to build models reflecting its inactive state.

Homology modeling of class A GPCRs: Probing the impact of agonist-bound and blocker-bound templates

254th National Meeting (2017)

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