Crystal structure of the GLP-1 receptor bound to a peptide agonist

Jazayeri, Ali; Rappas, Mathieu; Brown, Alastair; Kean, James; Errey, James C.; Robertson, NJ; Fiez-Vandal, Cédric; Andrews, Stephen P.; Congreve, Miles; Bortolato, Andrea; Mason, Jonathan S.; Baig, Asma; Teobald, Iryna; Dore, A.S.; Weir, Malcolm; Cooke, Robert M.; Marshall, Fiona H.

doi:10.1038/nature22800

Cited by 165 publications

(215 citation statements)

References 47 publications

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“…The mechanistic origin of the selective activation displayed by α/β-peptides 1 and 2 is unclear at present, due to the lack of structural characterization of PTHR1 or PTHR2. Nevertheless, structural data for other class B GPCRs allow us to formulate a mechanistic hypothesis (49)(50)(51). The transmembrane (TM) domains of class B GPCRs adopt a unique "V-shaped" structure and present a ligand-binding pocket that is more open toward the extracellular side relative to the pockets of class A GPCRs (52).…”

Section: Resultsmentioning

confidence: 99%

Receptor selectivity from minimal backbone modification of a polypeptide agonist

Liu

Cheloha

Watanabe

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Human parathyroid hormone (PTH) and N-terminal fragments thereof activate two receptors, hPTHR1 and hPTHR2, which share ∼51% sequence similarity. A peptide comprising the first 34 residues of PTH is fully active at both receptors and is used to treat osteoporosis. We have used this system to explore the hypothesis that backbone modification of a promiscuous peptidic agonist can provide novel receptor-selective agonists. We tested this hypothesis by preparing a set of variants of PTH(1–34)-NH2 that contained a single β-amino-acid residue replacement at each of the first eight positions. These homologs, each containing one additional backbone methylene unit relative to PTH(1–34)-NH2 itself, displayed a wide range of potencies in cell-based assays for PTHR1 or PTHR2 activation. The β-scan series allowed us to identify two homologs, each containing two α→β replacements, that were highly selective, one for PTHR1 and the other for PTHR2. These findings suggest that backbone modification of peptides may provide a general strategy for achieving activation selectivity among polypeptide-modulated receptors, and that success requires consideration of both β2- and β3-residues, which differ in terms of side-chain location.

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Section: Resultsmentioning

confidence: 99%

Receptor selectivity from minimal backbone modification of a polypeptide agonist

Liu

Cheloha

Watanabe

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…The future for novel peptides may be to follow the lead for the GLP‐1 receptor, where a ligand has been designed based on a crystal structure of the receptor (Jazayeri et al, ). A number of structures are available showing the ECDs of CLR/RAMP complexes or the CTR in complex with bound ligands (Table , Figure 8).…”

Section: Developments With Agonistsmentioning

confidence: 99%

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25

Hay

Garelja

Poyner

et al. 2017

British J Pharmacology

295

441

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The calcitonin/CGRP family of peptides includes calcitonin, α and β CGRP, amylin, adrenomedullin (AM) and adrenomedullin 2/intermedin (AM2/IMD). Their receptors consist of one of two GPCRs, the calcitonin receptor (CTR) or the calcitonin receptor-like receptor (CLR). Further diversity arises from heterodimerization of these GPCRs with one of three receptor activity-modifying proteins (RAMPs). This gives the CGRP receptor (CLR/RAMP1), the AM and AM receptors (CLR/RAMP2 or RAMP3) and the AMY AMY and AMY receptors (CTR/RAMPs1-3 complexes, respectively). Apart from the CGRP receptor, there are only peptide antagonists widely available for these receptors, and these have limited selectivity, thus defining the function of each receptor in vivo remains challenging. Further challenges arise from the probable co-expression of CTR with the CTR/RAMP complexes and species-dependent splice variants of the CTR (CT and CT ). Furthermore, the AMY receptor is activated equally well by both amylin and CGRP, and the preferred receptor for AM2/IMD has been unclear. However, there are clear therapeutic rationales for developing agents against the various receptors for these peptides. For example, many agents targeting the CGRP system are in clinical trials, and pramlintide, an amylin analogue, is an approved therapy for insulin-requiring diabetes. This review provides an update on the pharmacology of the calcitonin family of peptides by members of the corresponding subcommittee of the International Union of Basic and Clinical Pharmacology and colleagues.

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“…The ECD of GCGRapo has a distinct conformation compared to that of GCGRpept which represents the canonical peptide-bound conformation as seen in several Class B1 GPCRs (Supporting Material Fig. S3) (51)(52)(53)(54)(55)(56)(57)(58). The stalk in GCGRapo also forms a β-sheet with ECL1.…”

Section: Open and Closed Conformations Of The Ecdmentioning

confidence: 99%

The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor

Ansell

Song

Sansom

2020

Preprint

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The extracellular domain (ECD) of Class B1 G-protein coupled receptors (GPCRs) plays a central role in signal transduction and is uniquely positioned to sense both the extracellular and membrane environments. Whilst recent studies suggest a role for membrane lipids in the modulation of Class A and Class F GPCR signalling properties, little is known about the effect of lipids on Class B1 receptors. In this study, we employed multiscale molecular dynamics (MD) simulations to access the dynamics of the glucagon receptor (GCGR) ECD in the presence of native-like membrane bilayers.Simulations showed that the ECD could move about a hinge region formed by residues Q122-E126 to adopt both closed and open conformations relative to the TMD. ECD movements were modulated by binding of the glycosphingolipid GM3. These large-scale fluctuations in ECD conformation that may affect the ligand binding and receptor activation properties. We also identify a unique PIP2 interaction profile near ICL2/TM3 at the G-protein coupling interface, suggesting a mechanism of engaging G-proteins which may have a distinct dependence on PIP2 compared to Class A GPCRs.Given the structural conservation of Class B1 GPCRs, the modulatory effects of GM3 and PIP2 on GCGR may be conserved across these receptors, offering new insights into potential therapeutic targeting. Statement of SignificanceThe role of lipids in regulation of Class B GPCRs remains elusive, despite recent structural advances. In this study, multi-scale molecular dynamics simulations are used to evaluate lipid interactions with the glucagon receptor, a Class B1 GPCR. We find that the glycosphingolipid GM3 binds to the glucagon receptor extracellular domain (ECD), modulating the dynamics of the ECD and promoting movement away from the transmembrane domain . We also identify a unique PIP2 interaction fingerprint in a region known to be important for bridging G-protein coupling in Class A GPCRs. Thus, this study provides molecular insight into the behaviour of the glucagon receptor in a complex lipid bilayer environment which may aid understanding of glucagon receptor signalling properties.GCGR_main text v16 figs MS biorxiv.docx

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Crystal structure of the GLP-1 receptor bound to a peptide agonist

Cited by 165 publications

References 47 publications

Receptor selectivity from minimal backbone modification of a polypeptide agonist

Receptor selectivity from minimal backbone modification of a polypeptide agonist

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25

The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor

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