Agonist binding by the β2-adrenergic receptor: an effect of receptor conformation on ligand association-dissociation characteristics
Abstract
The β2-adrenergic receptor (β2-AR), a G protein-coupled receptor (GPCR), is a physiologically important transmembrane protein that is a target for drugs used for treatment of asthma and cardiovascular diseases. Study of the first steps of ligand recognition and the molecular basis of ligand binding to the orthosteric site is essential for understanding the pharmacological properties of the receptor. In this work we investigated the characteristic features of the agonist association-dissociation process to and from the different conformational forms of β2-AR by use of advanced molecular modeling techniques. The investigation was focused on estimating the free energy profiles (FEPs) corresponding to the process of a full agonist ((R,R)-fenoterol) and an inverse agonist (carazolol) binding and unbinding to and from β2-AR. The two different conformational forms of β2-AR, i.e. active β2-AR-PDB: 3P0G and inactive β2-AR-PDB: 2RH1 were included in this stage of the study. We revealed several significant qualitative differences between FEPs characteristic of both conformational forms. Both FEPs suggest the existence of three transient binding sites in the extracellular domain of β2-AR. Comparison of the residues surrounding these transi...Continue Reading
References
Dynamics of the beta2-adrenergic G-protein coupled receptor revealed by hydrogen-deuterium exchange.
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