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- PDB-8cls: Drosophila melanogaster insulin receptor ectodomain in complex wi... -

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Basic information

Entry
Database: PDB / ID: 8cls
TitleDrosophila melanogaster insulin receptor ectodomain in complex with DILP5
Components
  • Insulin-like receptor
  • Probable insulin-like peptide 5
  • Probable insulin-like peptide 5 A chain
KeywordsSIGNALING PROTEIN / DILP5 hormone / Drosophila insulin-like signalling receptor / disulfide linked ectodomain
Function / homology
Function and homology information


primary spermatocyte growth / negative regulation of peptide hormone secretion / Extra-nuclear estrogen signaling / germ-line stem-cell niche homeostasis / negative regulation of entry into reproductive diapause / Insulin signaling pathway / Insulin receptor recycling / female mating behavior / response to anoxia / male germ-line stem cell asymmetric division ...primary spermatocyte growth / negative regulation of peptide hormone secretion / Extra-nuclear estrogen signaling / germ-line stem-cell niche homeostasis / negative regulation of entry into reproductive diapause / Insulin signaling pathway / Insulin receptor recycling / female mating behavior / response to anoxia / male germ-line stem cell asymmetric division / embryonic development via the syncytial blastoderm / female germ-line stem cell population maintenance / germ-band shortening / negative regulation of circadian sleep/wake cycle, sleep / carbohydrate homeostasis / imaginal disc growth / open tracheal system development / germ-line stem cell division / positive regulation of neuron remodeling / follicle cell of egg chamber development / lymph gland development / intestinal stem cell homeostasis / female germ-line stem cell asymmetric division / positive regulation of border follicle cell migration / positive regulation of fat cell proliferation / positive regulation of organ growth / positive regulation of lipid storage / insulin receptor complex / positive regulation of multicellular organism growth / regulation of organ growth / insulin receptor activity / sleep / triglyceride homeostasis / embryo development ending in birth or egg hatching / insulin binding / positive regulation of wound healing / negative regulation of feeding behavior / positive regulation of neuroblast proliferation / female gonad development / lipid homeostasis / positive regulation of cell size / regulation of multicellular organism growth / insulin receptor substrate binding / developmental growth / phosphatidylinositol 3-kinase binding / cell surface receptor protein tyrosine kinase signaling pathway / cellular response to starvation / negative regulation of autophagy / response to cocaine / locomotory behavior / cholesterol homeostasis / determination of adult lifespan / axon guidance / insulin receptor binding / multicellular organism growth / hormone activity / receptor protein-tyrosine kinase / SH3 domain binding / circadian rhythm / insulin receptor signaling pathway / glucose homeostasis / nervous system development / regulation of cell population proliferation / positive regulation of cell growth / protein tyrosine kinase activity / response to oxidative stress / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor ligand activity / axon / protein phosphorylation / positive regulation of cell population proliferation / extracellular space / extracellular region / ATP binding / identical protein binding / metal ion binding / plasma membrane
Similarity search - Function
Insulin-related peptide, invertebrates / Long hematopoietin receptor, single chain family signature. / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Insulin family / Insulin/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. / Insulin-like / Insulin / insulin-like growth factor / relaxin family. ...Insulin-related peptide, invertebrates / Long hematopoietin receptor, single chain family signature. / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Insulin family / Insulin/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. / Insulin-like / Insulin / insulin-like growth factor / relaxin family. / 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-like receptor / Probable insulin-like peptide 5
Similarity search - Component
Biological speciesDrosophila melanogaster (fruit fly)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsViola, C.M. / Brzozowski, A.M. / Shafi, T.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/R009066/1 United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/W003783/1 United Kingdom
CitationJournal: Nat Commun / Year: 2023
Title: Structural conservation of insulin/IGF signalling axis at the insulin receptors level in Drosophila and humans.
Authors: Cristina M Viola / Orsolya Frittmann / Huw T Jenkins / Talha Shafi / Pierre De Meyts / Andrzej M Brzozowski /
Abstract: The insulin-related hormones regulate key life processes in Metazoa, from metabolism to growth, lifespan and aging, through an evolutionarily conserved insulin signalling axis (IIS). In humans the ...The insulin-related hormones regulate key life processes in Metazoa, from metabolism to growth, lifespan and aging, through an evolutionarily conserved insulin signalling axis (IIS). In humans the IIS axis is controlled by insulin, two insulin-like growth factors, two isoforms of the insulin receptor (hIR-A and -B), and its homologous IGF-1R. In Drosophila, this signalling engages seven insulin-like hormones (DILP1-7) and a single receptor (dmIR). This report describes the cryoEM structure of the dmIR ectodomain:DILP5 complex, revealing high structural homology between dmIR and hIR. The excess of DILP5 yields dmIR complex in an asymmetric 'T' conformation, similar to that observed in some complexes of human IRs. However, dmIR binds three DILP5 molecules in a distinct arrangement, showing also dmIR-specific features. This work adds structural support to evolutionary conservation of the IIS axis at the IR level, and also underpins a better understanding of an important model organism.
History
DepositionFeb 17, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 20, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Insulin-like receptor
B: Insulin-like receptor
C: Probable insulin-like peptide 5 A chain
D: Probable insulin-like peptide 5
E: Probable insulin-like peptide 5 A chain
F: Probable insulin-like peptide 5
G: Probable insulin-like peptide 5 A chain
H: Probable insulin-like peptide 5


Theoretical massNumber of molelcules
Total (without water)257,5908
Polymers257,5908
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area18590 Å2
ΔGint-114 kcal/mol
Surface area90120 Å2
MethodPISA

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Components

#1: Protein Insulin-like receptor / dIR / dInr / dIRH


Mass: 120074.641 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Drosophila melanogaster (fruit fly) / Gene: InR, dinr, Dir-a, Inr-a, CG18402 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P09208, receptor protein-tyrosine kinase
#2: Protein/peptide Probable insulin-like peptide 5 A chain


Mass: 2795.097 Da / Num. of mol.: 3 / Source method: obtained synthetically / Source: (synth.) Drosophila melanogaster (fruit fly) / References: UniProt: Q7KUD5
#3: Protein/peptide Probable insulin-like peptide 5 / dILP5 / Insulin-related peptide 5


Mass: 3018.603 Da / Num. of mol.: 3 / Source method: obtained synthetically / Source: (synth.) Drosophila melanogaster (fruit fly) / References: UniProt: Q7KUD5

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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

Component
IDNameTypeEntity IDParent-IDSource
1Drosophila insulin receptor ectodomain with DILP-5COMPLEXall0RECOMBINANT
2Drosophila insulin-like peptide 5COMPLEX#2-#31NATURAL
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.240 MDaNO
210.0058 MDaNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Drosophila melanogaster (fruit fly)7227
32Drosophila melanogaster (fruit fly)7227
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Spodoptera frugiperda (fall armyworm)7108
32Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid 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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 4000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 0.829 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
Image scansWidth: 5760 / Height: 4092

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 129444 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Details: Local fitting of Alphafold predicted domains was done using ChimeraX
RefinementResolution: 4→172.25 Å / Cor.coef. Fo:Fc: 0.983 / SU B: 23.071 / SU ML: 0.31 / ESU R: 0.48
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.24465 --
obs0.24465 118144 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 217.696 Å2
Refinement stepCycle: 1 / Total: 14494
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00714607
ELECTRON MICROSCOPYf_angle_d0.82519762
ELECTRON MICROSCOPYf_dihedral_angle_d14.3275410
ELECTRON MICROSCOPYf_chiral_restr0.0532179
ELECTRON MICROSCOPYf_plane_restr0.0112585
LS refinement shellResolution: 4→4.104 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.725 8737 -
obs--100 %

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