Probing the Mechanism of Receptor Activity–Modifying Protein Modulation of GPCR Ligand Selectivity through Rational Design of Potent Adrenomedullin and Calcitonin Gene-Related Peptide Antagonists

• Published in: Molecular pharmacology Vol. 93; no. 4; pp. 355 - 367
• Main Authors: Booe, Jason M., Warner, Margaret L., Roehrkasse, Amanda M., Hay, Debbie L., Pioszak, Augen A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2018; American Society for Pharmacology and Experimental Therapeutics; The American Society for Pharmacology and Experimental Therapeutics
• Subjects: Adrenomedullin - genetics; Adrenomedullin - metabolism; Amino Acid Sequence; Animals; Calcitonin Gene-Related Peptide - antagonists & inhibitors; Calcitonin Gene-Related Peptide - genetics; Calcitonin Gene-Related Peptide - metabolism; Chlorocebus aethiops; COS Cells; Drug Design; Humans; Ligands; Protein Structure, Secondary; Receptor Activity-Modifying Protein 1 - antagonists & inhibitors; Receptor Activity-Modifying Protein 1 - genetics; Receptor Activity-Modifying Protein 1 - metabolism; Receptor Activity-Modifying Protein 2 - antagonists & inhibitors; Receptor Activity-Modifying Protein 2 - genetics; Receptor Activity-Modifying Protein 2 - metabolism; Receptor Activity-Modifying Protein 3 - antagonists & inhibitors; Receptor Activity-Modifying Protein 3 - genetics; Receptor Activity-Modifying Protein 3 - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; MR; ECD; CLR; FP; AM; Ahx; BSA; DMEM; FITC; RAMP; AMmut; CGRPmut; MBP; CGRP

Binding of the vasodilator peptides adrenomedullin (AM) and calcitonin gene–related peptide (CGRP) to the class B G protein–coupled receptor calcitonin receptor–like receptor (CLR) is modulated by receptor activity–modifying proteins (RAMPs). RAMP1 favors CGRP, whereas RAMP2 and RAMP3 favor AM. Crys...