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- PDB-7u23: Single-chain LCDV-1 viral insulin-like peptide bound to IGF-1R ec... -

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Basic information

Entry
Database: PDB / ID: 7u23
TitleSingle-chain LCDV-1 viral insulin-like peptide bound to IGF-1R ectodomain, leucine-zippered form
Components
  • Insulin-like growth factor 1 receptor
  • single-chain LCDV-1 viral insulin-like peptide
KeywordsSIGNALING PROTEIN / IGF-1R ectodomain / inhibitor / viral insulin-like peptide / single-chain LCDV-1
Function / homology
Function and homology information


cardiac atrium development / negative regulation of cholangiocyte apoptotic process / insulin-like growth factor receptor activity / positive regulation of steroid hormone biosynthetic process / protein kinase complex / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / insulin-like growth factor binding / protein transporter activity / negative regulation of muscle cell apoptotic process ...cardiac atrium development / negative regulation of cholangiocyte apoptotic process / insulin-like growth factor receptor activity / positive regulation of steroid hormone biosynthetic process / protein kinase complex / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / insulin-like growth factor binding / protein transporter activity / negative regulation of muscle cell apoptotic process / cellular response to progesterone stimulus / positive regulation of DNA metabolic process / cellular response to zinc ion starvation / cellular response to aldosterone / insulin receptor complex / cellular response to testosterone stimulus / negative regulation of hepatocyte apoptotic process / insulin-like growth factor I binding / insulin receptor activity / transcytosis / alphav-beta3 integrin-IGF-1-IGF1R complex / response to alkaloid / Respiratory syncytial virus (RSV) attachment and entry / regulation of JNK cascade / cellular response to angiotensin / positive regulation of protein-containing complex disassembly / dendritic spine maintenance / cellular response to insulin-like growth factor stimulus / insulin binding / response to L-glutamate / negative regulation of MAPK cascade / establishment of cell polarity / positive regulation of axon regeneration / amyloid-beta clearance / positive regulation of osteoblast proliferation / positive regulation of cytokinesis / peptidyl-tyrosine autophosphorylation / insulin receptor substrate binding / estrous cycle / G-protein alpha-subunit binding / response to vitamin E / SHC-related events triggered by IGF1R / cellular response to dexamethasone stimulus / phosphatidylinositol 3-kinase binding / cellular response to transforming growth factor beta stimulus / T-tubule / cellular response to estradiol stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of smooth muscle cell proliferation / cerebellum development / axonogenesis / insulin-like growth factor receptor signaling pathway / caveola / hippocampus development / receptor protein-tyrosine kinase / cellular response to glucose stimulus / insulin receptor binding / response to nicotine / cellular response to mechanical stimulus / cellular senescence / cellular response to amyloid-beta / insulin receptor signaling pathway / positive regulation of cold-induced thermogenesis / protein tyrosine kinase activity / response to ethanol / protein autophosphorylation / Extra-nuclear estrogen signaling / receptor complex / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cell migration / immune response / axon / intracellular membrane-bounded organelle / neuronal cell body / positive regulation of cell population proliferation / negative regulation of apoptotic process / protein-containing complex binding / signal transduction / ATP binding / identical protein binding / membrane / plasma membrane
Similarity search - Function
Tyrosine-protein kinase, insulin-like receptor / 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 / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. ...Tyrosine-protein kinase, insulin-like receptor / 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 / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Growth factor receptor cysteine-rich domain superfamily / : / Fibronectin type III domain / 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. / Protein kinase domain profile. / Protein kinase domain / Immunoglobulin-like fold / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Insulin-like growth factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Lymphocystis disease virus 1
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.6 Å
AuthorsKirk, N.S. / Lawrence, M.C.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01DK031036 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)K01DK11796 United States
CitationJournal: Nat Commun / Year: 2022
Title: Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist.
Authors: Francois Moreau / Nicholas S Kirk / Fa Zhang / Vasily Gelfanov / Edward O List / Martina Chrudinová / Hari Venugopal / Michael C Lawrence / Veronica Jimenez / Fatima Bosch / John J Kopchick ...Authors: Francois Moreau / Nicholas S Kirk / Fa Zhang / Vasily Gelfanov / Edward O List / Martina Chrudinová / Hari Venugopal / Michael C Lawrence / Veronica Jimenez / Fatima Bosch / John J Kopchick / Richard D DiMarchi / Emrah Altindis / C Ronald Kahn /
Abstract: Lymphocystis disease virus-1 (LCDV-1) and several other Iridoviridae encode viral insulin/IGF-1 like peptides (VILPs) with high homology to human insulin and IGFs. Here we show that while single- ...Lymphocystis disease virus-1 (LCDV-1) and several other Iridoviridae encode viral insulin/IGF-1 like peptides (VILPs) with high homology to human insulin and IGFs. Here we show that while single-chain (sc) and double-chain (dc) LCDV1-VILPs have very low affinity for the insulin receptor, scLCDV1-VILP has high affinity for IGF1R where it can antagonize human IGF-1 signaling, without altering insulin signaling. Consequently, scLCDV1-VILP inhibits IGF-1 induced cell proliferation and growth hormone/IGF-1 induced growth of mice in vivo. Cryo-electron microscopy reveals that scLCDV1-VILP engages IGF1R in a unique manner, inducing changes in IGF1R conformation that led to separation, rather than juxtaposition, of the transmembrane segments and hence inactivation of the receptor. Thus, scLCDV1-VILP is a natural peptide with specific antagonist properties on IGF1R signaling and may provide a new tool to guide development of hormonal analogues to treat cancers or metabolic disorders sensitive to IGF-1 without affecting glucose metabolism.
History
DepositionFeb 22, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 16, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
E: Insulin-like growth factor 1 receptor
F: Insulin-like growth factor 1 receptor
C: single-chain LCDV-1 viral insulin-like peptide
D: single-chain LCDV-1 viral insulin-like peptide


Theoretical massNumber of molelcules
Total (without water)231,3284
Polymers231,3284
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 Insulin-like growth factor 1 receptor / Insulin-like growth factor I receptor / IGF-I receptor


Mass: 108937.242 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IGF1R / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: P08069, receptor protein-tyrosine kinase
#2: Protein single-chain LCDV-1 viral insulin-like peptide


Mass: 6726.710 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Lymphocystis disease virus 1

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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: 2:1 complex of scLCDV-1 and IGF-1Rzip / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
Buffer solutionpH: 8
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen 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: 2000 nm / Nominal defocus min: 500 nm / Alignment procedure: COMA FREE
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Detector mode: COUNTING / 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: cryoSPARC / Category: 3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 89000 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00412394
ELECTRON MICROSCOPYf_angle_d0.59816810
ELECTRON MICROSCOPYf_dihedral_angle_d14.7424606
ELECTRON MICROSCOPYf_chiral_restr0.0481852
ELECTRON MICROSCOPYf_plane_restr0.0032186

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