ArticleNature structural & molecular biology2023
Structural basis of the alkaline pH-dependent activation of insulin receptor-related receptor.
Article in Nature structural & molecular biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 16 citations in OpenAlex.
- DeepIR-Pred: identification of insulin receptors using metaheuristic optimization of biologically informed multi-view features with deep recurrent learning.Briefings in bioinformatics · 2026Article
- Insulin Receptor-Related Receptor Activation by Artificial Double-ER Mutations in the Transmembrane Domain.International journal of molecular sciences · 2026Article
- Structural insights into the activation of the chicken ROS1 receptor by the NEL/NICOL ligand complex.Nature communications · 2026Article
- Regulation and function of insulin and insulin-like growth factor receptor signalling.Nature reviews. Molecular cell biology · 2025Review
- Reanalysis of cryo-EM data reveals ALK-cytokine assemblies with both 2:1 and 2:2 stoichiometries.PLoS biology · 2025Article
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- Article
- Structures and pH-dependent dimerization of the sevenless receptor tyrosine kinase.Molecular cell · 2024Article
- Molecular basis of proton-sensing by G protein-coupled receptors.bioRxiv : the preprint server for biology · 2024Article
- Pendrin: linking acid base to blood pressure.Pflugers Archiv : European journal of physiology · 2024Review
- Activation of the insulin receptor by insulin-like growth factor 2.Nature communications · 2024Article
- Multi-tissue transcriptome-wide association study identifies novel candidate susceptibility genes for cataract.Frontiers in ophthalmology · 2024Article
- How protons pave the way to aggressive cancers.Nature reviews. Cancer · 2023Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
The insulin receptor (IR) family is a subfamily of receptor tyrosine kinases that controls metabolic homeostasis and cell growth. Distinct from IR and insulin-like growth factor 1 receptor, whose activation requires ligand binding, insulin receptor-related receptor (IRR)-the third member of the IR family-is activated by alkaline pH. However, the molecular mechanism underlying alkaline pH-induced IRR activation remains unclear. Here, we present cryo-EM structures of human IRR in both neutral pH inactive and alkaline pH active states. Combined with mutagenesis and cellular assays, we show that, upon pH increase, electrostatic repulsion of the pH-sensitive motifs of IRR disrupts its autoinhibited state and promotes a scissor-like rotation between two protomers, leading to a T-shaped active conformation. Together, our study reveals an unprecedented alkaline pH-dependent activation mechanism of IRR, opening up opportunities to understand the structure-function relationship of this important receptor.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.