A structural basis for amylin receptor phenotype

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

doi:10.1126/science.abm9609

A structural basis for amylin receptor phenotype

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

Drug Discovery Biology

Research output: Contribution to journal › Article › Research › peer-review

33 Citations (Scopus)

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.

Original language	English
Article number	eabm9609
Number of pages	14
Journal	Science
Volume	375
Issue number	6587
DOIs	https://doi.org/10.1126/science.abm9609
Publication status	Published - 25 Mar 2022

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10.1126/science.abm9609

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@article{a5e5ed5331714c76b29003808cfd2133,

title = "A structural basis for amylin receptor phenotype",

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.",

author = "Jianjun Cao and Belousoff, {Matthew J.} and Liang, {Yi Lynn} and Johnson, {Rachel M.} and Josephs, {Tracy M.} and Fletcher, {Madeleine M.} and Arthur Christopoulos and Hay, {Debbie L.} and Radostin Danev and Denise Wootten and Sexton, {Patrick M.}",

note = "Funding Information: This work was supported by the Monash University Ramaciotti Centre for Cryo-Electron Microscopy and the Monash MASSIVE high-performance computing facility. Figures were created with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health grant R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. This work was also funded by the Australian Research Council (ARC Centre grant IC200100052 to P.M.S. and D.W.); the National Health and Medical Research Council of Australia (NHMRC project grant 1120919 to P.M.S.; NHMRC project grant 1159006 to D.W.; NHMRC program grant 1150083 to P.M.S. and A.C.; NHMRC senior principal research fellowship 1154434 to P.M.S.; and NHMRC senior research fellowship 1155302 to D.W.); the Victoria Endowment for Science Knowledge and Innovation (fellowship to T.M.J.); the Takeda Science Foundation (2019 Medical Research Grant to R.D.); and the Japan Science and Technology Agency (PRESTO grant 18069571 to R.D.). Author Funding Information: Funding: This work was supported by the Monash University Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved.",

year = "2022",

month = mar,

day = "25",

doi = "10.1126/science.abm9609",

language = "English",

volume = "375",

journal = "Science",

issn = "0036-8075",

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T1 - A structural basis for amylin receptor phenotype

AU - Cao, Jianjun

AU - Belousoff, Matthew J.

AU - Liang, Yi Lynn

AU - Johnson, Rachel M.

AU - Josephs, Tracy M.

AU - Fletcher, Madeleine M.

AU - Christopoulos, Arthur

AU - Hay, Debbie L.

AU - Danev, Radostin

AU - Wootten, Denise

AU - Sexton, Patrick M.

N1 - Funding Information: This work was supported by the Monash University Ramaciotti Centre for Cryo-Electron Microscopy and the Monash MASSIVE high-performance computing facility. Figures were created with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health grant R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. This work was also funded by the Australian Research Council (ARC Centre grant IC200100052 to P.M.S. and D.W.); the National Health and Medical Research Council of Australia (NHMRC project grant 1120919 to P.M.S.; NHMRC project grant 1159006 to D.W.; NHMRC program grant 1150083 to P.M.S. and A.C.; NHMRC senior principal research fellowship 1154434 to P.M.S.; and NHMRC senior research fellowship 1155302 to D.W.); the Victoria Endowment for Science Knowledge and Innovation (fellowship to T.M.J.); the Takeda Science Foundation (2019 Medical Research Grant to R.D.); and the Japan Science and Technology Agency (PRESTO grant 18069571 to R.D.). Author Funding Information: Funding: This work was supported by the Monash University Publisher Copyright: Copyright © 2022 The Authors, some rights reserved.

PY - 2022/3/25

Y1 - 2022/3/25

N2 - 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.

AB - 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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U2 - 10.1126/science.abm9609

DO - 10.1126/science.abm9609

M3 - Article

C2 - 35324283

AN - SCOPUS:85127065073

SN - 0036-8075

VL - 375

JO - Science

JF - Science

IS - 6587

M1 - eabm9609

ER -

A structural basis for amylin receptor phenotype

Abstract

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Other files and links

A structural understanding of calcitonin gene-related peptide and adrenomedullin function

NHMRC Research Fellowship

Novel targeting of the glucagon family of G protein coupled receptors

Centre for Electron Microscopy (MCEM)

MASSIVE

Ramaciotti Centre for Cryo-Electron Microscopy

Cite this

A structural basis for amylin receptor phenotype

Abstract

UN SDGs

Access to Document

Other files and links

Projects

A structural understanding of calcitonin gene-related peptide and adrenomedullin function

NHMRC Research Fellowship

Novel targeting of the glucagon family of G protein coupled receptors

Equipment

Centre for Electron Microscopy (MCEM)

MASSIVE

Ramaciotti Centre for Cryo-Electron Microscopy

Cite this