An investigation into the origin of the biased agonism associated with the urotensin II receptor activation

Abstract

The urotensin II receptor (UTR) has long been studied mainly for its involvement in the cardiovascular homeostasis both in health and disease state. Two endogenous ligands activate UTR, i.e. urotensin II (U-II) and urotensin II-related peptide (URP). Extensive expression of the two ligands uncovers the diversified pathophysiological effects mediated by the urotensinergic system such as cardiovascular disorders, smooth muscle cell proliferation, renal disease, diabetes, and tumour growth. As newly reported, U-II and URP have distinct effects on transcriptional activity, cell proliferation, and myocardial contractile activities supporting the idea that U-II and URP interact with UTR in a distinct manner (biased agonism). To shed light on the origin of the divergent activities of the two endogenous ligands, we performed a conformational study on URP by solution NMR in sodium dodecyl sulfate micelle solution and compared the obtained NMR structure of URP with that of hU-II previously determined. Finally, we undertook docking studies between URP, hU-II, and an UT receptor model.

Structure–Activity Study of the Peptides P5U and Urantide by the Development of Analogues Containing Uncoded Amino Acids at Position 9

“…The lowest-energy NMR structure of peptide 4 was then docked into a model of UT built by homology. [44] Docking results (Figure 3 a) show that peptide 4 binds within the helical bundle among helices TM3-TM7, establishing multiple interactions with the receptor reported in Figure 3 b. For comparison, NMR structures of the full agonist P5U [23] and of the antagonist urantide [25] were also docked within the same receptor model (Supporting Information, Figure S2).…”

New directions for urotensin II receptor ligands

“…Accordingly, truncation of this region did not alter its binding affinity, its ability to modulate intracellular calcium mobilization or its vasocontractile action . However, we and others recently demonstrated the existence of specific interactions between this N‐terminal domain, and more particularly the aspartic and glutamic acid, and UT that could lead to specific topological changes in UT conformation and therefore subtle changes in UT activation . Supporting the role of the N‐terminal domain in the recognition and activation processes, it is interesting to note that the hUII counterpart of the aforementioned UCA modulators, i.e., [Pep 7 ]hUII, acted as a weak but full agonist of the UT receptor .…”

“…The N‐terminal domain of UII was generally deemed unimportant for the function of UII. However, the existence of an initial interaction was recently demonstrated between this N‐terminal domain, and more particularly the glutamic acid at position 1 and the aspartic acid at position 4, and UT that could lead to specific topological changes associated with UT activation . UII and URP are therefore expected to select/stabilize particular UT active conformations, thereby introducing texture in their activation profile, a feature referred to as biased agonism or functional selectivity .…”

Conformation and Dynamics of Human Urotensin II and Urotensin Related Peptide in Aqueous Solution

“…All NMR investigations show the N-terminal tail to be more flexible than the ring. URP has been suggested from the NMR experiments by Chatenet et al 15 to have an inverse 4,5,6 γ-turn 31 however, suggest structural flexibility in aqueous solution and a high similarity of URP and UII ring conformations. Carotenuto et al 28 made NMR studies of UII and the smaller URP-like version, UII (4)(5)(6)(7)(8)(9)(10)(11), in sodium dodecyl sulfate (SDS) micelles mimicking a cell-surface environment.…”

“…Analogous experiments for URP in SDS micelles suggested a very similar structure. 31 We now report unrestrained molecular dynamics (MD) simulations of human UII and URP with the Amber ff99sb force field on extended time scales (see Table S1 and Figures S1-S6 61 Here, we used REMD to determine equilibrium populations, rather than the metadynamics. This substitution is tested here.…”