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A structural basis for amylin receptor phenotype.

Cao J, Belousoff MJ, Liang YL, Johnson RM, Josephs TM, Fletcher MM, Christopoulos A, Hay DL, Danev R, Wootten D, Sexton PM
Science 375 eabm9609 (2022)
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Cited: 14 times
EuropePMC logo PMID: 35324283

Abstract

Amylin receptors (AMYRs) are heterodimers of the calcitonin (CT) receptor (CTR) and one of three receptor activity-modifying proteins (RAMPs), AMY1R, AMY2R, and AMY3R. 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, AMY1R with salmon CT (sCT), AMY2R 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. The CT-bound AMYR complexes were distinct, overlapping the CT-bound CTR complexes. Our findings indicate that activation of AMYRs by CT-based peptides is distinct from their activation by amylin-based peptides. This has important implications for the development of AMYR therapeutics.

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Articles - 7tyl mentioned but not cited (1)

  1. New Insights into the Structure and Function of Class B1 GPCRs. Cary BP, Zhang X, Cao J, Johnson RM, Piper SJ, Gerrard EJ, Wootten D, Sexton PM. Endocr Rev 44 492-517 (2023)


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  2. Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors. Lu J, Piper SJ, Zhao P, Miller LJ, Wootten D, Sexton PM. Int J Mol Sci 23 8069 (2022)
  3. Calcitonin/PAC1 receptor splice variants: a blind spot in migraine research. Rees TA, Labastida-Ramírez A, Rubio-Beltrán E. Trends Pharmacol Sci 44 651-663 (2023)
  4. Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins. Kotliar IB, Lorenzen E, Schwenk JM, Hay DL, Sakmar TP. Pharmacol Rev 75 1-34 (2023)
  5. Membranes under the Magnetic Lens: A Dive into the Diverse World of Membrane Protein Structures Using Cryo-EM. Piper SJ, Johnson RM, Wootten D, Sexton PM. Chem Rev 122 13989-14017 (2022)

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  2. A phosphine-based redox method for direct conjugation of disulfides. Lu Y, You L, Chen C. Chem Commun (Camb) 58 12439-12442 (2022)
  3. Adrenomedullin 2/intermedin is a slow off-rate, long-acting endogenous agonist of the adrenomedullin2 G protein-coupled receptor. Babin KM, Karim JA, Gordon PH, Lennon J, Dickson A, Pioszak AA. J Biol Chem 299 104785 (2023)
  4. Itch receptor MRGPRX4 interacts with the receptor activity-modifying proteins. Kotliar IB, Ceraudo E, Kemelmakher-Liben K, Oren DA, Lorenzen E, Dodig-Crnković T, Horioka-Duplix M, Huber T, Schwenk JM, Sakmar TP. J Biol Chem 299 104664 (2023)
  5. Negative allosteric modulation of the glucagon receptor by RAMP2. Krishna Kumar K, O'Brien ES, Habrian CH, Latorraca NR, Wang H, Tuneew I, Montabana E, Marqusee S, Hilger D, Isacoff EY, Mathiesen JM, Kobilka BK. Cell 186 1465-1477.e18 (2023)
  6. Structural basis of signaling regulation of the human melanocortin-2 receptor by MRAP1. Luo P, Feng W, Ma S, Dai A, Wu K, Chen X, Yuan Q, Cai X, Yang D, Wang MW, Eric Xu H, Jiang Y. Cell Res 33 46-54 (2023)
  7. Structural insight into selectivity of amylin and calcitonin receptor agonists. Cao J, Belousoff MJ, Gerrard E, Danev R, Fletcher MM, Dal Maso E, Schreuder H, Lorenz K, Evers A, Tiwari G, Besenius M, Li Z, Johnson RM, Wootten D, Sexton PM. Nat Chem Biol (2023)


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