Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G...

Area of Science:

• Structural biology
• Molecular pharmacology
• GPCR signaling

Background:

• Receptor activity-modifying proteins (RAMPs) associate with the calcitonin receptor-like receptor (CLR) to confer selectivity for calcitonin gene-related peptide (CGRP) and adrenomedullin (AM).
• The precise mechanisms by which peptides selectively bind CLR:RAMP complexes remain elusive.

Purpose of the Study:

• To elucidate the structural basis of CGRP and AM peptide binding to CLR:RAMP complexes.
• To understand how RAMPs modulate ligand recognition and receptor conformation.

Main Methods:

• X-ray crystallography of CLR:RAMP1 and CLR:RAMP2 extracellular domain heterodimers bound to CGRP analog and AM, respectively.
• Pharmacological characterization of ligand binding and receptor activation.

Main Results:

• Crystal structures reveal peptides binding a shared site on CLR, adopting a β-turn conformation near their C termini.
• RAMPs provide distinct contacts to variable peptide residues, influencing CLR conformation.
• Structural and pharmacological data demonstrate RAMP-mediated modulation of GPCR ligand binding.

Conclusions:

• The study provides atomic-level detail on how RAMPs fine-tune CLR binding specificity and conformation.
• These findings offer a structural framework for developing targeted therapeutics for CLR:RAMP-mediated pathways.