Jianjun Cao, Matthew J Belousoff, Yi-Lynn Liang, Rachel M Johnson, Tracy M Josephs, Madeleine M Fletcher, Arthur Christopoulos, Debbie L Hay, Radostin Danev, Denise Wootten, Patrick M Sexton
Amylin receptors (AMYRs) are heterodimers of the calcitonin (CT) receptor (CTR) and one of three receptor activity-modifying proteins (RAMPs), AMY1 R, AMY2 R, and AMY3 R. Selective AMYR agonists and dual AMYR/CTR agonists are being developed as obesity treatments; however, the molecular basis for peptide binding and selectivity is unknown. We determined the structure and dynamics of active AMYRs with amylin, AMY1 R with salmon CT (sCT), AMY2 R with sCT or human CT (hCT), and CTR with amylin, sCT, or hCT. The conformation of amylin-bound complexes was similar for all AMYRs, constrained by the RAMP, and an ordered midpeptide motif that we call the bypass motif...
March 25, 2022: Science