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- PDB-7u6d: Head region of insulin receptor ectodomain (A-isoform) bound to t... -

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Basic information

Entry
Database: PDB / ID: 7u6d
TitleHead region of insulin receptor ectodomain (A-isoform) bound to the non-insulin agonist IM459
Components
  • IM459
  • Isoform Short of Insulin receptor
KeywordsSIGNALING PROTEIN/AGONIST / insulin receptor / insulin-mimic peptide / insulin receptor agonist / SIGNALING PROTEIN-AGONIST complex
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 / male sex determination / insulin receptor complex / insulin-like growth factor I binding / positive regulation of protein-containing complex disassembly / insulin receptor activity / exocrine pancreas development ...regulation of female gonad development / positive regulation of meiotic cell cycle / insulin-like growth factor II binding / positive regulation of developmental growth / male sex determination / insulin receptor complex / insulin-like growth factor I binding / positive regulation of protein-containing complex disassembly / insulin receptor activity / exocrine pancreas development / dendritic spine maintenance / cargo receptor activity / insulin binding / adrenal gland development / PTB domain binding / neuronal cell body membrane / Signaling by Insulin receptor / IRS activation / positive regulation of respiratory burst / amyloid-beta clearance / regulation of embryonic development / insulin receptor substrate binding / positive regulation of receptor internalization / epidermis development / protein kinase activator activity / positive regulation of glycogen biosynthetic process / Signal attenuation / heart morphogenesis / transport across blood-brain barrier / phosphatidylinositol 3-kinase binding / Insulin receptor recycling / insulin-like growth factor receptor binding / dendrite membrane / neuron projection maintenance / positive regulation of mitotic nuclear division / receptor-mediated endocytosis / Insulin receptor signalling cascade / positive regulation of glycolytic process / positive regulation of D-glucose import across plasma membrane / learning / receptor protein-tyrosine kinase / caveola / receptor internalization / cellular response to growth factor stimulus / memory / male gonad development / cellular response to insulin stimulus / positive regulation of nitric oxide biosynthetic process / insulin receptor signaling pathway / late endosome / glucose homeostasis / amyloid-beta binding / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / lysosome / positive regulation of canonical NF-kappaB signal transduction / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of MAPK cascade / endosome membrane / positive regulation of cell migration / G protein-coupled receptor signaling pathway / protein domain specific binding / axon / external side of plasma membrane / positive regulation of cell population proliferation / regulation of DNA-templated transcription / symbiont entry into host cell / positive regulation of DNA-templated transcription / GTP binding / protein-containing complex binding / extracellular exosome / ATP binding / identical protein binding / membrane / plasma membrane
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. / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain ...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. / 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 / Fibronectin type III domain / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.03 Å
AuthorsKirk, N.S. / Lawrence, M.C.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Nat Commun / Year: 2022
Title: Activation of the human insulin receptor by non-insulin-related peptides.
Authors: Nicholas S Kirk / Qi Chen / Yingzhe Ginger Wu / Anastasia L Asante / Haitao Hu / Juan F Espinosa / Francisco Martínez-Olid / Mai B Margetts / Faiz A Mohammed / Vladislav V Kiselyov / David ...Authors: Nicholas S Kirk / Qi Chen / Yingzhe Ginger Wu / Anastasia L Asante / Haitao Hu / Juan F Espinosa / Francisco Martínez-Olid / Mai B Margetts / Faiz A Mohammed / Vladislav V Kiselyov / David G Barrett / Michael C Lawrence /
Abstract: The human insulin receptor signalling system plays a critical role in glucose homeostasis. Insulin binding brings about extensive conformational change in the receptor extracellular region that in ...The human insulin receptor signalling system plays a critical role in glucose homeostasis. Insulin binding brings about extensive conformational change in the receptor extracellular region that in turn effects trans-activation of the intracellular tyrosine kinase domains and downstream signalling. Of particular therapeutic interest is whether insulin receptor signalling can be replicated by molecules other than insulin. Here, we present single-particle cryoEM structures that show how a 33-mer polypeptide unrelated to insulin can cross-link two sites on the receptor surface and direct the receptor into a signalling-active conformation. The 33-mer polypeptide engages the receptor by two helical binding motifs that are each potentially mimicable by small molecules. The resultant conformation of the receptor is distinct from-but related to-those in extant three-dimensional structures of the insulin-complexed receptor. Our findings thus illuminate unexplored pathways for controlling the signalling of the insulin receptor as well as opportunities for development of insulin mimetics.
History
DepositionMar 3, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 5, 2022Provider: repository / Type: Initial release
Revision 1.0Oct 5, 2022Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 5, 2022Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 5, 2022Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 5, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 5, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1May 28, 2025Group: Data collection / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / em_software / pdbx_entry_details / pdbx_modification_feature / struct_conn
Item: _em_admin.last_update / _em_software.name ..._em_admin.last_update / _em_software.name / _pdbx_entry_details.has_protein_modification / _struct_conn.pdbx_leaving_atom_flag
Revision 1.1May 28, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: IM459
C: Isoform Short of Insulin receptor
B: Isoform Short of Insulin receptor


Theoretical massNumber of molelcules
Total (without water)213,2163
Polymers213,2163
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein/peptide IM459


Mass: 4000.595 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#2: Protein Isoform Short of Insulin receptor / IR


Mass: 104607.664 Da / Num. of mol.: 2 / Fragment: ectodomain (UNP residues 28-943)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INSR / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: P06213, receptor protein-tyrosine kinase
Has ligand of interestN
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: Complex of non-insulin insulin receptor agonist IM459 bound to the insulin receptor ectodomain (A-isoform) construct IR-A(ecto)
Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: 4000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 69.5 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 5.03 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 184000 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0027308
ELECTRON MICROSCOPYf_angle_d0.5199896
ELECTRON MICROSCOPYf_dihedral_angle_d12.3162715
ELECTRON MICROSCOPYf_chiral_restr0.0441069
ELECTRON MICROSCOPYf_plane_restr0.0031272

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