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- PDB-9ef1: Cryo-EM structure of Drosophila melanogaster insulin receptor (dm... -

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Basic information

Entry
Database: PDB / ID: 9ef1
TitleCryo-EM structure of Drosophila melanogaster insulin receptor (dmIR) bound with one DILP1, asymmetric conformation
Components
  • DILP1 A-chain
  • DILP1 B-chain
  • Insulin-like receptor
KeywordsSTRUCTURAL PROTEIN / Insulin receptor / DILP
Function / homology
Function and homology information


primary spermatocyte growth / negative regulation of peptide hormone secretion / Extra-nuclear estrogen signaling / response to anoxia / negative regulation of entry into reproductive diapause / Insulin signaling pathway / Insulin receptor recycling / female mating behavior / embryonic development via the syncytial blastoderm / male germ-line stem cell asymmetric division ...primary spermatocyte growth / negative regulation of peptide hormone secretion / Extra-nuclear estrogen signaling / response to anoxia / negative regulation of entry into reproductive diapause / Insulin signaling pathway / Insulin receptor recycling / female mating behavior / embryonic development via the syncytial blastoderm / male germ-line stem cell asymmetric division / female germ-line stem cell population maintenance / germ-band shortening / carbohydrate homeostasis / germ-line stem-cell niche homeostasis / imaginal disc growth / open tracheal system development / positive regulation of neuron remodeling / germ-line stem cell division / negative regulation of circadian sleep/wake cycle, sleep / lymph gland development / follicle cell of egg chamber development / positive regulation of border follicle cell migration / female germ-line stem cell asymmetric division / positive regulation of fat cell proliferation / intestinal stem cell homeostasis / growth cone membrane / positive regulation of organ growth / positive regulation of lipid storage / insulin receptor complex / regulation of organ growth / insulin receptor activity / embryo development ending in birth or egg hatching / positive regulation of multicellular organism growth / insulin binding / triglyceride homeostasis / negative regulation of feeding behavior / positive regulation of wound healing / negative regulation of macroautophagy / positive regulation of neuroblast proliferation / female gonad development / lipid homeostasis / insulin receptor substrate binding / regulation of multicellular organism growth / developmental growth / positive regulation of cell size / phosphatidylinositol 3-kinase binding / positive regulation of TORC1 signaling / axon guidance / cholesterol homeostasis / cellular response to starvation / determination of adult lifespan / insulin receptor binding / response to cocaine / locomotory behavior / circadian rhythm / receptor protein-tyrosine kinase / hormone activity / SH3 domain binding / multicellular organism growth / insulin receptor signaling pathway / nervous system development / glucose homeostasis / regulation of cell population proliferation / protein autophosphorylation / positive regulation of cell growth / response to oxidative stress / protein tyrosine kinase activity / protein phosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / axon / positive regulation of cell population proliferation / extracellular space / extracellular region / ATP binding / metal ion binding / identical protein binding / plasma membrane
Similarity search - Function
Long hematopoietin receptor, single chain family signature. / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. / Insulin, conserved site / Insulin family signature. / Insulin-like superfamily ...Long hematopoietin receptor, single chain family signature. / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / 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 / 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
Insulin-like receptor / Insulin-like peptide 1
Similarity search - Component
Biological speciesDrosophila melanogaster (fruit fly)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsBai, X.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Nat Commun / Year: 2025
Title: Structure and activation of the Drosophila insulin receptor by three Drosophila insulin-like peptides.
Authors: Kai Cai / Michelle Ng / Rochele R Yamamoto / Mohammed Akhter Hossain / Catherine Hall / John D Wade / Marc Tatar / Eunhee Choi / Xiao-Chen Bai /
Abstract: Insulin/IGF signaling (IIS) is a highly conserved pathway essential for physiological regulation from yeast to mammals. In Drosophila melanogaster, a single insulin-like receptor (dmIR) interacts ...Insulin/IGF signaling (IIS) is a highly conserved pathway essential for physiological regulation from yeast to mammals. In Drosophila melanogaster, a single insulin-like receptor (dmIR) interacts with various insulin-like peptides (DILPs), leading to diverse signaling and functional outcomes. However, the mechanisms by which different DILPs result in varied receptor activation and biological responses remain unclear. Here, we determine the cryo-electron microscopy (cryo-EM) structures of dmIR in complex with three DILPs: DILP1, DILP2, and DILP5. Our structural analyses reveal that each DILP induces distinct conformations of dmIR: the dmIR/DILP5 complex adopts the Ƭ-shaped asymmetric conformation with three bound DILP5 molecules; the dmIR/DILP2 complex displays the Γ-shaped asymmetric conformation with a single bound DILP2 molecule; and the dmIR/DILP1 complex shows both a Γ-shaped asymmetric conformation and a symmetric conformation that resembles a T-shape with a splayed stem. Functional assays demonstrate that the efficacy of DILP-mediated dmIR activation differs, with DILP5 inducing higher levels of receptor autophosphorylation, followed by DILP2 and DILP1. Together, these findings suggest that the distinct interactions between dmIR and DILPs dictate specific patterns of receptor activation.
History
DepositionNov 19, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 1, 2025Provider: repository / Type: Initial release
Revision 1.0Oct 1, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 1, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 1, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 1, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 1, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Nov 12, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: DILP1 B-chain
D: DILP1 A-chain
A: Insulin-like receptor
B: Insulin-like receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)490,08016
Polymers487,4264
Non-polymers2,65412
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein/peptide DILP1 B-chain / dILP1 / Insulin-related peptide 1


Mass: 4243.928 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Drosophila melanogaster (fruit fly) / References: UniProt: Q9VT50
#2: Protein/peptide DILP1 A-chain


Mass: 3025.562 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Drosophila melanogaster (fruit fly) / References: UniProt: Q9VT50
#3: Protein Insulin-like receptor / dIR / dInr / Insulin receptor homolog / dIRH / Receptor protein-tyrosine kinase InR


Mass: 240078.078 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Drosophila melanogaster (fruit fly) / Gene: InR, Dir-a, Inr-a, IR, CG18402 / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: P09208, receptor protein-tyrosine kinase
#4: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestY
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: Drosophila melanogaster insulin receptor in complex with DILP1, asymmetric conformation
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Drosophila melanogaster (fruit fly)
Source (recombinant)Organism: Baculovirus expression vector pFastBac1-HM
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELIONparticle selection
2SerialEM4.1image acquisition
8PHENIXmodel refinement
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 23556 / Symmetry type: POINT
RefinementHighest resolution: 4.4 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00211638
ELECTRON MICROSCOPYf_angle_d0.58615753
ELECTRON MICROSCOPYf_dihedral_angle_d7.0331613
ELECTRON MICROSCOPYf_chiral_restr0.0441785
ELECTRON MICROSCOPYf_plane_restr0.0042028

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