8f2a

Human Amylin3 Receptor in complex with Gs and Pramlintide analogue peptide San385 (Cluster 5 conformation)Human Amylin3 Receptor in complex with Gs and Pramlintide analogue peptide San385 (Cluster 5 conformation)

Structural highlights

8f2a is a 7 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.2Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RAMP3_HUMAN Plays a role in cardioprotection by reducing cardiac hypertrophy and perivascular fibrosis in a GPER1-dependent manner. Transports the calcitonin gene-related peptide type 1 receptor (CALCRL) and GPER1 to the plasma membrane. Acts as a receptor for adrenomedullin (AM) together with CALCRL.^[1] ^[2]

Publication Abstract from PubMed

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 AMY(3)R, and San45 bound to AMY(3)R 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 AMY(3)R. Targeted lipid modification may provide a single intervention strategy for design of long-acting, nonselective, Amy-based DACRAs with potential anti-obesity effects.

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. 2024 Feb;20(2):162-169. doi: 10.1038/s41589-023-01393-4. Epub 2023 , Aug 3. PMID:37537379^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lenhart PM, Broselid S, Barrick CJ, Leeb-Lundberg LM, Caron KM. G-protein-coupled receptor 30 interacts with receptor activity-modifying protein 3 and confers sex-dependent cardioprotection. J Mol Endocrinol. 2013 Jul 3;51(1):191-202. doi: 10.1530/JME-13-0021. Print 2013. PMID:23674134 doi:http://dx.doi.org/10.1530/JME-13-0021
↑ McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature. 1998 May 28;393(6683):333-9. PMID:9620797 doi:10.1038/30666
↑ 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. Structural insight into selectivity of amylin and calcitonin receptor agonists. Nat Chem Biol. 2024 Feb;20(2):162-169. PMID:37537379 doi:10.1038/s41589-023-01393-4

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OCA

[1] Lenhart PM, Broselid S, Barrick CJ, Leeb-Lundberg LM, Caron KM. G-protein-coupled receptor 30 interacts with receptor activity-modifying protein 3 and confers sex-dependent cardioprotection. J Mol Endocrinol. 2013 Jul 3;51(1):191-202. doi: 10.1530/JME-13-0021. Print 2013. PMID:23674134 doi:http://dx.doi.org/10.1530/JME-13-0021

[2] McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature. 1998 May 28;393(6683):333-9. PMID:9620797 doi:10.1038/30666

[3] 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. Structural insight into selectivity of amylin and calcitonin receptor agonists. Nat Chem Biol. 2024 Feb;20(2):162-169. PMID:37537379 doi:10.1038/s41589-023-01393-4

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