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    • br Model of receptor binding and activation It

    2020-08-06


    Model of receptor binding and activation It has been proposed that ETAs display an inactive conformation (R) or an active conformation (R*) that can bind one or more G proteins (G) and other Methicillin sodium salt mg proteins (Figure 1a). An orthosteric agonist (e.g. ET1) binds sequentially and polyvalently to R and promotes its activation (R→R* conversion). A first transitory complex (R-et) is a prerequisite for subsequent formation of the quasi-irreversible R-ET complex (Figure 1b). Although R-et binding and G-R*-et function might exhibit typical class A GPCR behavior, R-ET binding and G-R*-ET function do not. The initial transitory complexes might exhibit dynamic equilibrium and susceptibility to desensitization and tolerance. By contrast, the ultimate complexes are tight and their effects are long-lasting and persistent (Figure 1b). Figure 1c,d illustrates the effects of a neutral competitive antagonist and an allosteric modulator in this situation, respectively. Recent work by our research team revealed functional observations [16] that, in combination with earlier structure–affinity relationships 25, 34, suggest roles for different parts of the agonist molecule and different domains of ETA in (i) the dynamic interaction, (ii) ultimate tight binding and (iii) activation of the receptor. We therefore propose that ET1 consists of two functional parts (Figure 2). One part of the agonist would be responsible for association with ETA. This would concentrate another part of the agonist at another domain of the receptor, which could then bind tightly and activate the receptor. For various other endogenous peptides that act on class B GPCRs, the reported structure–activity relationships are in line with the presence of distinct ‘address’ and ‘message’ domains 35, 36, 37, 38. For ET1, such detailed information is not available yet, but structural analyses indicate a flexibility of the agonist molecule [25] that might be essential for the two parts of the agonist to interact sequentially with ETA (Figure 2). In the event that ET1 consists of functional parts separated by a hinge region [25], the orthosteric binding site of ETA contains at least two functional domains (Figure 2). This suggestion is supported by studies using engineered receptors and photoaffinity labeling 27, 28, 29, 30, 34. During the past decade, it became increasingly clear that the affinity and efficacy of small agonists acting on the orthosteric binding site of a GPCR can be modulated by ligands that bind to a topographically distinct (allosteric) binding site on the same GPCR molecule 33, 39, 40, 41, 42. This allosteric modulation involves cooperativity between the affinity and efficacy of the distinct ligands acting on their distinct binding sites. In our opinion, a large agonist molecule such as ET1 that consists of two parts and that acts on two orthosteric binding domains of a receptor engages similar cooperativity between the orthosteric binding domains (Figure 2); in other words, endothelins might be considered as endogenous bitopic agonists [43] of at least ETA.