Commentary on: Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound Beta 1- Adrenergic Receptor

G protein coupled receptors (GPCRs) comprise a large superfamily of transmembrane proteins containing more than 800 unique family members [1,2]. Critically, GPCRs mediate most of the cell responses to extracellular stimuli including hormones, neurotransmitters, light, taste, etc. Adrenergic receptors (ARs) bind with norepinephrine and epinephrine and are expressed in many organs, especially in heart [3,4]. Nonetheless, heart failure is one of the major contributions to mortality in the developed countries and the downregulation of ARs is commonly observed in the heart failure patients [5]. Therefore, ARs are significant regulators in cardiac activities. There are 12 subtypes of ARs, beta-1 adrenergic receptor (β1AR) and beta-2 adrenergic receptor (β2AR) are the most important subtypes, which both coupled with Gs protein. Previous mutagenesis studies disclosed a few key residues of ARs that interact with the agonist, which provide piece of information for drug discovery [6,7]. To understand the whole picture of ligand binding and interaction with G proteins, structural determination of ARs is necessary. The β2AR-Gs complex structure published in 2011 shined the light on the protein interaction and the conformational changes upon activation [8]. However, β1AR is the predominant receptor, accounting for approximately 80% in the adult human heart [3]. The structure determination of β1AR-Gs complex is more desirable in the drug design of heart diseases. The recent published paper ” Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound β1-Adrenergic Receptor” reported the high-resolution structure of β1AR in complex with Gs protein using cryo-EM method and investigated the molecular mechanism of Gs protein activation induced by β1AR, which unveil more structural information to facilitate the drug discovery of human heart diseases [9].