A structural basis for amylin receptor phenotype.

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• Amylin receptors (AMYRs) are heterodimers of calcitonin receptors (CTRs) and receptor activity-modifying proteins (RAMPs).
• AMYRs and CTRs are targets for obesity treatments, but the molecular basis of their peptide binding and selectivity remains unclear.
• Understanding these interactions is vital for rational drug design.

Purpose of the Study:

• To determine the structure and dynamics of active AMYRs bound to amylin and CT-based peptides.
• To elucidate the molecular mechanisms underlying peptide binding and selectivity at AMYRs and CTRs.
• To inform the development of novel therapeutics targeting AMYRs.

Main Methods:

• Determined the cryo-electron microscopy structures of active AMYRs complexed with amylin.
• Determined structures of AMY₁R and AMY₂R with salmon CT (sCT) and human CT (hCT).
• Determined structures of CTR complexed with amylin, sCT, and hCT.

Main Results:

• Amylin-bound AMYR complexes adopted a conserved conformation, featuring a RAMP-constrained bypass motif.
• CT-bound AMYR complexes showed distinct structures compared to amylin-bound complexes.
• CT-bound AMYR structures overlapped with CT-bound CTR structures, indicating shared binding elements.

Conclusions:

• Activation of AMYRs by CT-based peptides differs mechanistically from activation by amylin.
• The identified structural differences provide insights into AMYR and CTR selectivity.
• These findings have significant implications for the therapeutic development of AMYR agonists for obesity and other metabolic disorders.