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Structural insight into selectivity of amylin and calcitonin receptor agonists

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Abstract

Amylin receptors (AMYRs), heterodimers of the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins, are promising obesity targets. A hallmark of AMYR activation by Amy is the formation of a ‘bypass’ secondary structural motif (residues S19–P25). This study explored potential tuning of peptide selectivity through modification to residues 19–22, resulting in a selective AMYR agonist, San385, as well as nonselective dual amylin and calcitonin receptor agonists (DACRAs), with San45 being an exemplar. We determined the structure and dynamics of San385-bound AMY3R, and San45 bound to AMY3R or CTR. San45, via its conjugated lipid at position 21, was anchored at the edge of the receptor bundle, enabling a stable, alternative binding mode when bound to the CTR, in addition to the bypass mode of binding to AMY3R. Targeted lipid modification may provide a single intervention strategy for design of long-acting, nonselective, Amy-based DACRAs with potential anti-obesity effects.

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Fig. 1: Amino acid sequence of peptides discussed in this paper, displayed using single letter code.
Fig. 2: Cryo-EM maps and model comparison of active, Gs-coupled complexes of AMY3R and CTR bound to peptide agonists.
Fig. 3: The ‘dynamic’ bypass conformation of San385 bound to AMY3R.
Fig. 4: The alternative conformations of the mid-region of San45 bound to AMY3R and CTR complexes are facilitated by the membrane-anchoring effect of the lipidated K21.

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Data availability

The atomic coordinates and electron microscopy maps have been deposited in the Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) under accession codes: 8F0K/EMD-28759 (San385–AMY3R–DNGs complex), 8F2A/EMD-28810 (the cluster 5 conformation of the San385–AMY3R–DNGs complex), 8F0J/EMD-28758 (San45–CTR–DNGs complex) and 8F2B/EMD-28812 (San45–AMY3R–DNGs complex). Source data are provided with this paper.

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Acknowledgements

This work was funded by Australian Research Council (ARC) Centre grant no. IC200100052 (P.M.S. and D.W.), National Health and Medical Research Council of Australia (NHMRC) project grant no. 1120919 (P.M.S.), NHMRC project grant no. 1159006 (D.W.), NHMRC program grant no. 1150083 (P.M.S.), NHMRC Senior Principal Research Fellow 1154434 (P.M.S.), NHMRC Senior Research Fellow no. 1155302 (D.W.), Japan Society for the Promotion of Science (JSPS) Kakenhi grant (no. 22H02554) (R.D.). The work was supported by the Monash University Ramaciotti Centre for Cryo-Electron Microscopy, the Bio21 Ian Holmes Imaging Centre (The University of Melbourne) and the Monash MASSIVE high-performance computing facility. Figures were created with UCSF Chimera and 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 no. R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. We are grateful to Y.-L. Liang for assay and technical support and S. Piper for help with protein structure visualization.

Author information

Author notes

  1. Madeleine M. Fletcher

    Present address: GlaxoSmithKline, Abbotsford, Victoria, Australia

  2. Andreas Evers

    Present address: Merck Healthcare KGaA, Darmstadt, Germany

  3. Garima Tiwari

    Present address: Janssen Vaccines and Prevention B.V., Leiden, the Netherlands

  4. Rachel M. Johnson

    Present address: OMass Therapeutics, Oxford, UK

Authors and Affiliations

  1. Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

    Jianjun Cao, Matthew J. Belousoff, Elliot Gerrard, Madeleine M. Fletcher, Emma Dal Maso, Rachel M. Johnson, Denise Wootten & Patrick M. Sexton

  2. ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

    Jianjun Cao, Matthew J. Belousoff, Elliot Gerrard, Emma Dal Maso, Rachel M. Johnson, Denise Wootten & Patrick M. Sexton

  3. Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Radostin Danev

  4. Sanofi-Aventis Deutschland GmbH, R&D, Industriepark Hoechst, Frankfurt am Main, Germany

    Herman Schreuder, Katrin Lorenz, Andreas Evers, Garima Tiwari, Melissa Besenius & Ziyu Li

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Contributions

D.W., P.M.S. and H.S. conceptualized the study. J.C., E.D.M. and R.M.J. generated proteins used in the study. J.C., M.J.B., R.D. and R.M.J. collected and/or processed cryo-EM data. H.S., K.L., A.E., G.T., M.B. and Z.L. generated the new peptides and performed pharmacological analyses. M.M.F. and E.G. performed pharmacological assays. J.C., D.W., P.M.S. and M.J.B. provided interpretation of the data. J.C., M.J.B. and R.D. contributed to data visualization. P.M.S., D.W. and R.D. acquired funding for the research. P.M.S., D.W. and M.J.B. provided project supervision and administration. J.C. and P.M.S. wrote the original draft and all authors contributed to reviewing and editing of the manuscript.

Corresponding authors

Correspondence to Denise Wootten or Patrick M. Sexton.

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Competing interests

P.M.S. and D.W. are shareholders and P.M.S. is a co-founder of Septerna Inc. P.M.S. and D.W. are co-founders and shareholders of DACRA Therapeutics. H.S., K.L., A.E., G.T., M.B. and Z.L. are current or former employees of Sanofi. All other authors have no competing interests to declare.

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Extended data

Extended Data Fig. 1 Pharmacological characterization of peptides.

Concentration-response analysis of 30-min cAMP accumulation following peptide addition in (A) HEK293-Flp-In cell lines stably expressing CTR and AMY3R; and (B) COS-1 cells transiently expressing CTR, AMY1R, or AMY3R. Data were normalized to the response of forskolin (10−5 M) or salmon calcitonin (10−8 M) and fit with a three-parameter logistic equation. Values are means + S.E.M. of four experiments.

Source data

Extended Data Fig. 2 Purification and cryo-EM data imaging and processing of active, Gs-coupled AMY3R bound to San385.

Top left, exemplar cryo-EM 2D class averages. Top middle, local resolution-filtered EM maps (consensus; Å). Top right, Fourier shell correlation (FSC) curves for the final consensus maps and half map validation, showing the overall nominal resolution. Bottom left, SEC trace of post FLAG-affinity column elution. The main peak was isolated and analysed by SDS-PAGE (insert). Bottom middle, local resolution-filtered EM maps (ECD focused refinement) displaying local resolution (Å). Bottom right, FSC curves for the focused refinement maps. Data are from an individual biochemical preparation.

Source data

Extended Data Fig. 3 Purification and cryo-EM data imaging and processing of active, Gs-coupled complexes bound to San45.

(A) San45-AMY3R complex. (B) San45-CTR complex. Within each panel: Top left, exemplar 2D cryo-EM class averages. Top middle, local resolution-filtered EM maps (consensus; Å). Top right, Fourier shell correlation (FSC) curves for the final consensus maps and map validation from half maps, showing the overall nominal resolution. Bottom left, SEC trace of post FLAG-affinity column elution. The main peak was isolated and analysed by SDS-PAGE (insert). Bottom middle, local resolution-filtered EM maps (receptor focused refinements) displaying local resolution (Å). Bottom right, FSC curves for the focused refinement maps. Data are from individual biochemical preparations.

Source data

Extended Data Fig. 4 Conserved structural features of CTR and AMYR complexes bound to different peptides.

Conformations of the ECD of CTR and AMYR complexes aligned to the CTR ECD (A) and the conserved ordered water networks in the N-terminal peptide binding pockets (B) and the Gαs coupling interface (C). The structural waters are coloured the same as RAMP3 in AMY3R complexes or red in San45-CTR. Protein backbones are coloured according to the labelling on the panel and displayed in ribbon (A) or protein worm (B and C) format. Protein side chains are not displayed for clarity in visualisation of the water networks.

Extended Data Fig. 5 Superposition of backbone models of the receptor-G protein interface fitted into the two extreme maps from the main principal component of motion for the interface from 3DVA of each of the complexes.

Structures were aligned on the CTR protomer and measurement of the distance between the Cα of Q12Gɑs illustrates the extent of motion at the receptor-Gs protein interface.

Extended Data Fig. 6 3D particle subclassification of active, Gs-coupled AMY3R bound to San385, and map refinement for Cluster 5.

Top left, histogram of 10 particle clusters following masked 3D classification in Cryosparc. Clusters 4 and 5 (dashed red rectangle) exhibit a different conformation to the consensus map. Top right, receptor focused mask used in the 3D classification. Bottom, FSC curves and local resolution-filtered EM maps (receptor focused, left; consensus, right) derived from cluster 5.

Extended Data Fig. 7 The dynamic conformations of rAmy-CTR is likely correlated with lower stability of ECL3 arising from differences in the rotamer of W3616.58.

Map to model representation of the mid-region of rAmy bound to CTR in CT-like conformation (A) or bypass motif conformation (B); amino acids of the mid-region are shown in stick representation. Model comparison of TMD bundles for San45-CTR and rAmy-CTR (CT-like conformation) complexes (C) and San45-AMY3R and rAmy-CTR (bypass conformation) (D) highlighting the distinct rotamer position of W3616.58 (stick representation).

Extended Data Fig. 8 Duration of action analysis for lipidated and non-lipidated peptide analogues.

COS-7 cells transiently transfected with AMY1R were incubated with increasing concentrations of peptide agonists for 30 min (A) or 15 min (B) (grey shading) before removal of assay buffer and replacement with either assay buffer without peptide (A) or assay buffer containing 1 μM of the antagonist peptide, sCT(8–32) (B). The dashed red line in (B) illustrates the continued production of cAMP in the presence of San45 or sCT but not with San385 or San387. Data are mean ± S.E.M. of 3 (A) or 4 (B) independent experiments conducted in duplicate.

Source data

Supplementary information

Supplementary Information

Supplementary Tables 1 and 2 and Note.

Reporting Summary

Supplementary Video 1

3DVA of cryo-EM data of San385–AMY3R and San45–AMY3R G protein complexes, shown sequentially, illustrating similar conformational dynamics of the RAMP3 C terminus and ICL2 of the CTR protomer; the hydrophobic F256ICL2 is labeled. The map surface is coloured for individual protein components; red, RAMP3 (San385 complex), blue, CTR (San385 complex), orange, RAMP3 (San45 complex), light blue, CTR (San45 complex), gold, Gas ras domain, cyan, Gβ1, purple, Gγ2.

Supplementary Video 2

3DVA of the first principal component of motion illustrating dynamics of the receptor ECD and peptides for the San385–AMY3R complex. The map surface has been colored for individual protein components; red, RAMP3, green, San385 and blue, CTR.

Source data

Extended Data Fig. 1

Statistical source data.

Extended Data Fig. 2a

Unprocessed Coomassie-stained SDS–PAGE gel.

Extended Data Fig. 3

Unprocessed Coomassie-stained SDS–PAGE gel.

Extended Data Fig. 8

Statistical source data.

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Cao, J., Belousoff, M.J., Gerrard, E. et al. Structural insight into selectivity of amylin and calcitonin receptor agonists. Nat Chem Biol 20, 162–169 (2024). https://doi.org/10.1038/s41589-023-01393-4

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