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- PDB-7tym: Cryo-EM Structure of insulin receptor-related receptor (IRR) in a... -
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Open data
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Basic information
Entry | Database: PDB / ID: 7tym | |||||||||
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Title | Cryo-EM Structure of insulin receptor-related receptor (IRR) in active-state captured at pH 9. The 3D refinement was applied with C2 symmetry | |||||||||
![]() | Insulin receptor-related protein | |||||||||
![]() | SIGNALING PROTEIN / Receptor tyrosine kinase / insulin receptor family | |||||||||
Function / homology | ![]() cellular response to alkaline pH / male sex determination / insulin receptor complex / insulin receptor activity / insulin receptor substrate binding / transmembrane receptor protein tyrosine kinase activity / phosphatidylinositol 3-kinase binding / cell surface receptor protein tyrosine kinase signaling pathway / receptor protein-tyrosine kinase / actin cytoskeleton organization ...cellular response to alkaline pH / male sex determination / insulin receptor complex / insulin receptor activity / insulin receptor substrate binding / transmembrane receptor protein tyrosine kinase activity / phosphatidylinositol 3-kinase binding / cell surface receptor protein tyrosine kinase signaling pathway / receptor protein-tyrosine kinase / actin cytoskeleton organization / protein autophosphorylation / receptor complex / axon / ATP binding / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å | |||||||||
![]() | Wang, L.W. / Hall, C. / Li, J. / Choi, E. / Bai, X.C. | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Structural basis of the alkaline pH-dependent activation of insulin receptor-related receptor. Authors: Liwei Wang / Catherine Hall / Jie Li / Eunhee Choi / Xiao-Chen Bai / ![]() 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 ...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. | |||||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 323.6 KB | Display | ![]() |
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PDB format | ![]() | 251.3 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 26185MC ![]() 7tyjC ![]() 7tykC C: citing same article ( M: map data used to model this data |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 143879.547 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: P14616, receptor protein-tyrosine kinase |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Insulin receptor-related receptor (IRR) in active-state captured at pH 9 Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Molecular weight | Value: 0.14 MDa / Experimental value: NO |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 9 |
Specimen | Conc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE / Humidity: 100 % |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2600 nm / Nominal defocus min: 1600 nm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
EM imaging optics | Energyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV |
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Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 3034847 | |||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 79010 / Symmetry type: POINT | |||||||||||||||||||||||||||
Atomic model building | Protocol: AB INITIO MODEL / Space: REAL |