Activation of the insulin receptor by an insulin mimetic peptide

Park, Junhee; Li, Jie; Mayer, John P.; Ball, Kerri A.; Wu, Jiayi; Hall, Catherine; Accili, Domenico; Stowell, Michael H. B.; Bai, Xiao Chen; Choi, Eunhee

doi:10.1038/s41467-022-33274-0

Cited by 22 publications

(28 citation statements)

References 71 publications

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“…The IR and IGF1R signaling assay were performed as described earlier with some modifications ( Uchikawa et al, 2019 ; Li et al, 2022 ; Li et al, 2019 ; Park et al, 2022 ). For the activation assay, the short isoform of human IR and human IGF1R in pCS2-MYC were used as described previously ( Uchikawa et al, 2019 ; Li et al, 2019 ; Choi et al, 2016 ).…”

Section: Methodsmentioning

confidence: 99%

Molecular basis for the role of disulfide-linked αCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor

Hall

et al. 2022

eLife

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The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) control metabolic homeostasis and cell growth and proliferation. The IR and IGF1R form similar disulfide bonds linked homodimers in the apo-state; however, their ligand binding properties and the structures in the active state differ substantially. It has been proposed that the disulfide-linked C-terminal segment of α-chain (αCTs) of the IR and IGF1R control the cooperativity of ligand binding and regulate the receptor activation. Nevertheless, the molecular basis for the roles of disulfide-linked αCTs in IR and IGF1R activation are still unclear. Here, we report the cryo-EM structures of full-length mouse IGF1R/IGF1 and IR/insulin complexes with modified αCTs that have increased flexibility. Unlike the Γ-shaped asymmetric IGF1R dimer with a single IGF1 bound, the IGF1R with the enhanced flexibility of αCTs can form a T-shaped symmetric dimer with two IGF1s bound. Meanwhile, the IR with non-covalently linked αCTs predominantly adopts an asymmetric conformation with four insulins bound, which is distinct from the T-shaped symmetric IR. Using cell-based experiments, we further showed that both IGF1R and IR with the modified αCTs cannot activate the downstream signaling potently. Collectively, our studies demonstrate that the certain structural rigidity of disulfide-linked αCTs is critical for optimal IR and IGF1R signaling activation.

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Section: Methodsmentioning

confidence: 99%

Molecular basis for the role of disulfide-linked αCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor

Hall

et al. 2022

eLife

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“…Two binding sites equivalent to insulin's sites 1 and 2 have also been identified on IGF-I and II by site-directed mutagenesis (Gauguin et al, 2008;Alvino et al, 2009), with site 1 extending into their C-domain. The engagement of insulin/IGFs site 1 and 2 in hIR/mIR/IGF-1R binding was ultimately confirmed in the last decade in over 40 crystal and cryoEM structures of complexes of these hormones (as well as insulin mimetic peptides and aptamers) with their cognate receptors and their extensive functional studies ( Kavran et al, 2014, Croll et al, 2016Weis et al, 2018;Xu et al, 2018Xu et al, , 2020Xu et al, , 2022Scapin et al, 2018;Gutmann et al, 2018Gutmann et al, , 2020Uchikawa et al, 2019;Li et al, 2019Li et al, , 2022Blyth et al, 2020;Zhang et al, 2020Xiong et al, 2022;Nielsen et al, 2022;Wu et al, 2022; preprint (which was not certified by peer review) is the author/funder. All rights reserved.…”

Section: Introductionmentioning

confidence: 94%

“…3b). Such asymmetric insulin binding to the hIR was postulated as structurally unfeasible due to envisaged steric clashes between hormone molecules occupying simultaneously lower/dynamic-arm based site1 and static protomer site2' (Li et al, 2022). Therefore this two-hormones-down and onehormone up T asymmetric conformation of the DILP5:dmIR complex can be considered as a specific signalling form of the dmIR, especially as the supersaturated insulin:receptor conditions used yielded only T symmetrical hIR conformers (e.g., PDB SOF, 6PXW/6PXV) (Gutmann et al, 2020;Uchikawa et al, 2019).…”

Section: Overall Mode Of Dilp5 -Dmir-ecd Bindingmentioning

confidence: 99%

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Structural Conservation of Insulin/IGF Signalling Axis at the Insulin Receptors Level inDrosophilaand humans

Viola

Frittmann

Jenkins

et al. 2023

Preprint

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The family of insulin-related hormones regulates key life processes in Metazoa, from metabolism to growth, reproduction, lifespan and aging, through an evolutionarily conserved Insulin/insulin-like growth factor-1 (IGF-1) signalling (IIS) axis. In humans the IIS axis is controlled by insulin, two insulin-like growth factors, two isoforms of the insulin receptor (hIR-A and -B), its homologous IGF-1R and their hybrid dimers. In Drosophila, this signalling engages seven insulin-like proteins (DILP1-7) and a single receptor (dmIR), with many downstream proteins and pathways that are homologous with human ones. This report reveals the first cryoEM structure of the dmIR ectodomain:DILP5 complex providing the evidence of structural homology between dmIR and hIR. In the presence of excess hormone, the overall organisation of the dmIR complex is an asymmetric T conformation, similar to that observed in some human IR structures. However, dmIR binds three DILP5 molecules in an unseen arrangement, revealing unique structural signatures that could rationalize the selective binding and signalling by different DILPs. This work provides structural proof of the evolutionary conservation of key receptors of the insulin-like hormones signalling axis, underpinning a deeper understanding of an important model animal organism.

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“…Additional examples for the application of cryo-EM in SBDD can be found in ion channels such as Transient Receptor Potential Cation Channel Subfamily A Member 1 (TRPA1) [ 55 ] and Transient Receptor Potential cation channel subfamily V member 1 [ 56 ], gamma-aminobutyric acid receptor [ 57 , 58 ], insulin receptor [ 59 , 60 ], as well as biased GPCR ligands like GLP-1 receptor-Gs complex [ 61 ], mu-opioid receptor [ 62 ], non-covalent TRPA1-biased agonist GNE551 [ 63 , 64 ] and sphingosine-1-phosphate receptor 1 [ 65 ].…”

Section: Application Of Cryo-em In Sbddmentioning

confidence: 99%

Applications and prospects of cryo-EM in drug discovery

Zhu

Yuan

et al. 2023

Military Med Res

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Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time- and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy (cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence (AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of medium-resolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery.

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Activation of the insulin receptor by an insulin mimetic peptide

Cited by 22 publications

References 71 publications

Molecular basis for the role of disulfide-linked αCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor

Molecular basis for the role of disulfide-linked αCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor

Structural Conservation of Insulin/IGF Signalling Axis at the Insulin Receptors Level inDrosophilaand humans

Applications and prospects of cryo-EM in drug discovery

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