6hvk | pdb_00006hvk

Pepducin UT-Pep2 a biased allosteric agonist of Urotensin-II receptor

spinqualitylabelsall models 6hvk, 10 NMR models Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6hvk is a 1 chain structure. This structure supersedes the now removed PDB entry 6q8l. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. NonStd Res: ACE, NH2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [UR2R_HUMAN] High affinity receptor for urotensin-2 and urotensin-2B. The activity of this receptor is mediated by a G-protein that activate a phosphatidylinositol-calcium second messenger system. Publication Abstract from PubMed Over the last decade, the urotensinergic system, composed of one G protein-coupled receptor and two endogenous ligands, has garnered significant attention as a promising new target for the treatment of various cardiovascular diseases. Indeed, this system is associated with various biomarkers of cardiovascular dysfunctions and is involved in changes in cardiac contractility, fibrosis, and hypertrophy contributing, like the angiotensinergic system, to the pathogenesis and progression of heart failure. Significant investment has been made toward the development of clinically relevant UT ligands for therapeutic intervention, but with little or no success to date. This system therefore remains to be therapeutically exploited. Pepducins and other lipidated peptides have been used as both mechanistic probes and potential therapeutics; therefore, pepducins derived from the human urotensin II receptor might represent unique tools to generate signaling bias and study hUT signaling networks. Two hUT-derived pepducins, derived from the second and the third intracellular loop of the receptor (hUT-Pep2 and [Trp(1), Leu(2)]hUT-Pep3, respectively), were synthesized and pharmacologically characterized. Our results demonstrated that hUT-Pep2 and [Trp(1), Leu(2)]hUT-Pep3 acted as biased ago-allosteric modulators, triggered ERK1/2 phosphorylation and, to a lesser extent, IP1 production, and stimulated cell proliferation yet were devoid of contractile activity. Interestingly, both hUT-derived pepducins were able to modulate human urotensin II (hUII)- and urotensin II-related peptide (URP)-mediated contraction albeit to different extents. These new derivatives represent unique tools to reveal the intricacies of hUT signaling and also a novel avenue for the design of allosteric ligands selectively targeting hUT signaling potentially. Lipidated peptides derived from intracellular loops 2 and 3 of the urotensin II receptor act as biased allosteric ligands.,Nassour H, Hoang TA, Martin RD, Dallagnol JCC, Billard E, Letourneau M, Novellino E, Carotenuto A, Allen BG, Tanny JC, Fournier A, Hebert TE, Chatenet D J Biol Chem. 2021 Aug 10;297(3):101057. doi: 10.1016/j.jbc.2021.101057. PMID:34389356 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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