6HVB

NMR structure of Urotensin Peptide Asp-c[Cys-Phe-(N-Me)Trp-Lys-Tyr-Cys]-Val in SDS solution

Summary for 6HVB

• Entry DOI: 10.2210/pdb6hvb/pdb
• NMR Information: BMRB: 34319
• Descriptor: Urotensin-2 (1 entity in total)
• Functional Keywords: g protein-coupled receptor, urotensin ii receptor, nmr solutions, sds, n-methylation, peptide binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 1078.28

Authors

Brancaccio, D.,Carotenuto, A.,Merlino, F.,Billard, E.,Yousif, A.M.,Di Maro, S.,Abate, L.,Bellavita, R.,D'Emmanuele di Villa Bianca, R.,Santicioli, P.,Marinelli, L.,Novellino, E.,Hebert, T.E.,Lubell, W.D.,Chatenet, D.,Grieco, P. (deposition date: 2018-10-10, release date: 2019-01-16, Last modification date: 2023-06-14)

Primary citation

Merlino, F.,Billard, E.,Yousif, A.M.,Di Maro, S.,Brancaccio, D.,Abate, L.,Carotenuto, A.,Bellavita, R.,d'Emmanuele di Villa Bianca, R.,Santicioli, P.,Marinelli, L.,Novellino, E.,Hebert, T.E.,Lubell, W.D.,Chatenet, D.,Grieco, P.
Functional Selectivity Revealed by N-Methylation Scanning of Human Urotensin II and Related Peptides.
J.Med.Chem., 62:1455-1467, 2019

PubMed Abstract: In accordance with their common but also divergent physiological actions, human urotensin II (1) and urotensin II-related peptide (2) could stabilize specific urotensin II receptor (UTR) conformations, thereby activating different signaling pathways, a feature referred to as biased agonism or functional selectivity. Sequential N-methylation of the amides in the conserved core sequence of 1, 2, and fragment U-II (3) shed light on structural requirements involved in their functional selectivity. Thus, 18 N-methylated UTR ligands were synthesized and their biological profiles evaluated using in vitro competition binding assays, ex vivo rat aortic ring bioassays and BRET-based biosensor experiments. Biological activity diverged from that of the parent structures contingent on the location of amide methylation, indicating relevant hydrogen-bond interactions for the function of the endogenous peptides. Conformational analysis of selected N-methyl analogs indicated the importance of specific amide residues of 2 for the distinct pharmacology relative to 1 and 3.

PubMed: 30615452
DOI: 10.1021/acs.jmedchem.8b01601

Experimental method

SOLUTION NMR