Binding pathway determines norepinephrine selectivity for the human β1AR over β2AR

Mechanistic insights into dopaminergic and serotonergic neurotransmission – concerted interactions with helices 5 and 6 drive the functional outcome

“…The power of enhanced sampling techniques for capturing biologically relevant events has been shown in previous studies. [17][18][19] Here, we use this approach to construct the complete energetic binding landscape of dopamine and closely related signaling probes. The small size and low number of rotatable bonds of studied compounds allow for an exhaustive sampling of their binding.…”

Ligands of Adrenergic Receptors: A Structural Point of View

“…The passage in β1AR is continuously negatively charged, thus preferred by norepinephrine, while epinephrine, a secondary amine, is less affected. This hypothesis explains the fast association rate of norepinephrine in β1AR and is supported by free energy profiles, calculated using metadynamics simulations [43].…”

“…Mutations of N6.55 and S5.43 (which forms hydrogen bond to N6.55) in β 2 AR reduce the efficacy of full agonist isoproterenol, strongly supporting that this hydrogen bond network is crucial to the full activation of βARs [70]. All full agonists can form a hydrogen bond to N6.55, either by 3-hydroxy in catechol (like epinephrine [31,43] or isoproterenol [54,66]) or groups mimicking catechol (such as formoterol [11] or BI-167107 [8,43,90]). Most partial agonists cannot form this hydrogen bond for replacement of the 3-hydroxy, including salmeterol [70], salbutamol [54,69], xamoterol [54], and clenbuterol.…”

“…The benefits of subtype-selective drugs are also found in the other two major types: α 1A /α 1D selective antagonist tamsulosin has less impact on blood pressure while treating benign prostatic hyperplasia [38]; and α 2C selective antagonists are in development as potential treatments for multiple psychiatric diseases [39]. Positions 5.39 [40], 5.43 [41], 6.58 [42], 6.62 [43] (ECL3), 7.32 [42], and 7.35 [44,45] are reported to affect the subtype selectivity of ligands. These residues are at the extracellular edge of the pocket (Figures 2a and 3b,c).…”

Signaling and function of cardiac autonomic nervous system receptors: Insights from the GPCR signalling universe

“…b 1 AR is by far the predominant bAR subtype in human adult cardiac myocytes, representing 75-80% of the total bAR density, followed by the b 2 AR, which comprises about 15-18% of the total cardiomyocyte bAR complement and the remaining 2-3% is b 3 ARs [2,[28][29][30][31]. Of note, all a 1 -AR and a 2 -AR subtypes, as well as the b 1 AR, respond to both SNS neurotransmitters (NE and Epi) with equal affinity and efficiency, but only Epi (not NE) can efficiently activate the human b 2 AR subtype [7,32]. In direct contrast with the b 2 AR subtype, the b 3 AR is much more efficiently activated by NE than by Epi, to which it is barely responsive [7,33].…”