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- PDB-7qid: tentative model of the human insulin receptor ectodomain bound by... -

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Basic information

Entry
Database: PDB / ID: 7qid
Titletentative model of the human insulin receptor ectodomain bound by three insulin
Components
  • (Insulin) x 2
  • Insulin receptor
  • Isoform Short of Insulin receptor
KeywordsMEMBRANE PROTEIN / cell surface receptor / insulin / tyrosine kinase receptor / glucose homeostasis / hormone / diabetes
Function / homology
Function and homology information


regulation of female gonad development / positive regulation of meiotic cell cycle / insulin-like growth factor II binding / positive regulation of developmental growth / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly / adrenal gland development / dendritic spine maintenance ...regulation of female gonad development / positive regulation of meiotic cell cycle / insulin-like growth factor II binding / positive regulation of developmental growth / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly / adrenal gland development / dendritic spine maintenance / insulin binding / : / cargo receptor activity / negative regulation of glycogen catabolic process / negative regulation of fatty acid metabolic process / Signaling by Insulin receptor / PTB domain binding / IRS activation / Insulin processing / regulation of protein secretion / negative regulation of feeding behavior / positive regulation of peptide hormone secretion / negative regulation of acute inflammatory response / Regulation of gene expression in beta cells / positive regulation of respiratory burst / neuronal cell body membrane / alpha-beta T cell activation / amyloid-beta clearance / heart morphogenesis / positive regulation of receptor internalization / insulin receptor substrate binding / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of gluconeogenesis / negative regulation of protein secretion / positive regulation of dendritic spine maintenance / fatty acid homeostasis / positive regulation of brown fat cell differentiation / positive regulation of glycogen biosynthetic process / positive regulation of insulin receptor signaling pathway / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / positive regulation of lipid biosynthetic process / negative regulation of respiratory burst involved in inflammatory response / protein kinase activator activity / negative regulation of lipid catabolic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / nitric oxide-cGMP-mediated signaling / regulation of protein localization to plasma membrane / transport vesicle / phosphatidylinositol 3-kinase binding / transport across blood-brain barrier / Insulin receptor recycling / COPI-mediated anterograde transport / positive regulation of nitric-oxide synthase activity / negative regulation of reactive oxygen species biosynthetic process / insulin-like growth factor receptor binding / NPAS4 regulates expression of target genes / positive regulation of D-glucose import across plasma membrane / positive regulation of mitotic nuclear division / neuron projection maintenance / male gonad development / endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated endocytosis / positive regulation of glycolytic process / learning / Insulin receptor signalling cascade / regulation of embryonic development / dendrite membrane / endosome lumen / positive regulation of protein secretion / acute-phase response / positive regulation of cytokine production / wound healing / insulin receptor binding / positive regulation of long-term synaptic potentiation / positive regulation of neuron projection development / glucose metabolic process / positive regulation of cell differentiation / negative regulation of protein catabolic process / Regulation of insulin secretion / memory / regulation of synaptic plasticity / receptor protein-tyrosine kinase / hormone activity / positive regulation of protein localization to nucleus / vasodilation / caveola / Golgi lumen / cognition / insulin receptor signaling pathway / positive regulation of nitric oxide biosynthetic process / glucose homeostasis / cellular response to insulin stimulus / late endosome / regulation of protein localization / cell-cell signaling / protein autophosphorylation / positive regulation of cell growth / amyloid-beta binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
Similarity search - Function
Insulin receptor, trans-membrane domain / Insulin receptor trans-membrane segment / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Insulin / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. ...Insulin receptor, trans-membrane domain / Insulin receptor trans-membrane segment / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Insulin / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. / Insulin, conserved site / Insulin family signature. / Insulin-like superfamily / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / Fibronectin type 3 domain / : / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Insulin / Insulin receptor / Isoform Short of Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5 Å
AuthorsGutman, T. / Schaefer, I.B. / Poojari, C.S. / Vattulainen, I. / Strauss, M. / Coskun, U.
Funding supportEuropean Union, 4items
OrganizationGrant numberCountry
German Research Foundation (DFG)251981924TRR83European Union
German Research Foundation (DFG)347368302 FOR2682European Union
European Research Council (ERC)CROWDED-PRO-LIPIDSEuropean Union
Academy of FinlandEuropean Union
CitationJournal: J Cell Biol / Year: 2020
Title: Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain.
Authors: Theresia Gutmann / Ingmar B Schäfer / Chetan Poojari / Beate Brankatschk / Ilpo Vattulainen / Mike Strauss / Ünal Coskun /
Abstract: Glucose homeostasis and growth essentially depend on the hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current ...Glucose homeostasis and growth essentially depend on the hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current understanding of insulin ligand-receptor interactions. While biochemistry predicts two distinct insulin binding sites, 1 and 2, recent structural analyses have resolved only site 1. Using a combined approach of cryo-EM and atomistic molecular dynamics simulation, we present the structure of the entire dimeric insulin receptor ectodomain saturated with four insulin molecules. Complementing the previously described insulin-site 1 interaction, we present the first view of insulin bound to the discrete insulin receptor site 2. Insulin binding stabilizes the receptor ectodomain in a T-shaped conformation wherein the membrane-proximal domains converge and contact each other. These findings expand the current models of insulin binding to its receptor and of its regulation. In summary, we provide the structural basis for a comprehensive description of ligand-receptor interactions that ultimately will inform new approaches to structure-based drug design.
History
DepositionDec 14, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 2, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature

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Assembly

Deposited unit
A: Insulin receptor
B: Isoform Short of Insulin receptor
C: Insulin receptor
D: Isoform Short of Insulin receptor
E: Insulin
F: Insulin
K: Insulin
L: Insulin
I: Insulin
J: Insulin


Theoretical massNumber of molelcules
Total (without water)225,81110
Polymers225,81110
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Insulin receptor / IR


Mass: 82551.742 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INSR / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
References: UniProt: P06213, receptor protein-tyrosine kinase
#2: Protein Isoform Short of Insulin receptor / IR


Mass: 21627.248 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INSR / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
References: UniProt: P06213-2, receptor protein-tyrosine kinase
#3: Protein/peptide Insulin


Mass: 2383.698 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INS / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P01308
#4: Protein/peptide Insulin


Mass: 3433.953 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INS / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P01308
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: insulin receptor ectodomain with three insulin bound / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightValue: 0.37 MDa / Experimental value: YES
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3500 nm / Nominal defocus min: 500 nm
Image recordingAverage exposure time: 10.2 sec. / Electron dose: 55 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 51

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameVersionCategory
10RELION2.1initial Euler assignment
11RELION3final Euler assignment
12RELION3classification
13RELION33D reconstruction
CTF correctionType: NONE
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 50079 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00316221
ELECTRON MICROSCOPYf_angle_d0.62522021
ELECTRON MICROSCOPYf_dihedral_angle_d11.1076000
ELECTRON MICROSCOPYf_chiral_restr0.0442394
ELECTRON MICROSCOPYf_plane_restr0.0042870

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