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Yorodumi- PDB-7mqs: The insulin receptor ectodomain in complex with three venom hybri... -
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-Basic information
Entry | Database: PDB / ID: 7mqs | ||||||
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Title | The insulin receptor ectodomain in complex with three venom hybrid insulin molecules - asymmetric conformation | ||||||
Components |
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Keywords | HORMONE / TOXIN / insulin / receptor / venom / cone snail | ||||||
Function / homology | Function and homology information negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion ...negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of respiratory burst / positive regulation of peptide hormone secretion / Regulation of gene expression in beta cells / negative regulation of acute inflammatory response / alpha-beta T cell activation / negative regulation of respiratory burst involved in inflammatory response / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of protein secretion / regulation of protein localization to plasma membrane / fatty acid homeostasis / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of lipid catabolic process / negative regulation of gluconeogenesis / COPI-mediated anterograde transport / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / negative regulation of reactive oxygen species biosynthetic process / positive regulation of insulin receptor signaling pathway / nitric oxide-cGMP-mediated signaling / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / neuron projection maintenance / NPAS4 regulates expression of target genes / positive regulation of protein metabolic process / positive regulation of brown fat cell differentiation / positive regulation of glycolytic process / activation of protein kinase B activity / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / positive regulation of nitric-oxide synthase activity / positive regulation of cytokine production / positive regulation of long-term synaptic potentiation / Regulation of insulin secretion / acute-phase response / endosome lumen / positive regulation of protein secretion / positive regulation of glucose import / positive regulation of cell differentiation / negative regulation of proteolysis / regulation of transmembrane transporter activity / insulin-like growth factor receptor binding / wound healing / insulin receptor binding / regulation of synaptic plasticity / negative regulation of protein catabolic process / hormone activity / receptor protein-tyrosine kinase / cognition / positive regulation of neuron projection development / positive regulation of protein localization to nucleus / Golgi lumen / vasodilation / glucose metabolic process / regulation of protein localization / insulin receptor signaling pathway / cell-cell signaling / glucose homeostasis / positive regulation of NF-kappaB transcription factor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / secretory granule lumen / protease binding / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cell migration / G protein-coupled receptor signaling pathway / Amyloid fiber formation / endoplasmic reticulum lumen / Golgi membrane / negative regulation of gene expression / positive regulation of cell population proliferation / positive regulation of gene expression / regulation of DNA-templated transcription / extracellular space / extracellular region / identical protein binding Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.4 Å | ||||||
Authors | Blakely, A.D. / Xiong, X. / Kim, J.H. / Menting, J. / Schafer, I.B. / Schubert, H.L. / Agrawal, R. / Gutmann, T. / Delaine, C. / Zhang, Y. ...Blakely, A.D. / Xiong, X. / Kim, J.H. / Menting, J. / Schafer, I.B. / Schubert, H.L. / Agrawal, R. / Gutmann, T. / Delaine, C. / Zhang, Y. / Artik, G.O. / Merriman, A. / Eckert, D. / Lawrence, M.C. / Coskun, U. / Fisher, S.J. / Forbes, B.E. / Safavi-Hemami, H. / Hill, C.P. / Chou, D.H.C. | ||||||
Funding support | 1items
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Citation | Journal: Nat Chem Biol / Year: 2022 Title: Symmetric and asymmetric receptor conformation continuum induced by a new insulin. Authors: Xiaochun Xiong / Alan Blakely / Jin Hwan Kim / John G Menting / Ingmar B Schäfer / Heidi L Schubert / Rahul Agrawal / Theresia Gutmann / Carlie Delaine / Yi Wolf Zhang / Gizem Olay Artik / ...Authors: Xiaochun Xiong / Alan Blakely / Jin Hwan Kim / John G Menting / Ingmar B Schäfer / Heidi L Schubert / Rahul Agrawal / Theresia Gutmann / Carlie Delaine / Yi Wolf Zhang / Gizem Olay Artik / Allanah Merriman / Debbie Eckert / Michael C Lawrence / Ünal Coskun / Simon J Fisher / Briony E Forbes / Helena Safavi-Hemami / Christopher P Hill / Danny Hung-Chieh Chou / Abstract: Cone snail venoms contain a wide variety of bioactive peptides, including insulin-like molecules with distinct structural features, binding modes and biochemical properties. Here, we report an active ...Cone snail venoms contain a wide variety of bioactive peptides, including insulin-like molecules with distinct structural features, binding modes and biochemical properties. Here, we report an active humanized cone snail venom insulin with an elongated A chain and a truncated B chain, and use cryo-electron microscopy (cryo-EM) and protein engineering to elucidate its interactions with the human insulin receptor (IR) ectodomain. We reveal how an extended A chain can compensate for deletion of B-chain residues, which are essential for activity of human insulin but also compromise therapeutic utility by delaying dissolution from the site of subcutaneous injection. This finding suggests approaches to developing improved therapeutic insulins. Curiously, the receptor displays a continuum of conformations from the symmetric state to a highly asymmetric low-abundance structure that displays coordination of a single humanized venom insulin using elements from both of the previously characterized site 1 and site 2 interactions. | ||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7mqs.cif.gz | 315.3 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7mqs.ent.gz | 257.9 KB | Display | PDB format |
PDBx/mmJSON format | 7mqs.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7mqs_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 7mqs_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 7mqs_validation.xml.gz | 59.4 KB | Display | |
Data in CIF | 7mqs_validation.cif.gz | 88.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/mq/7mqs ftp://data.pdbj.org/pub/pdb/validation_reports/mq/7mqs | HTTPS FTP |
-Related structure data
Related structure data | 23951MC 7mqoC 7mqrC C: citing same article (ref.) M: map data used to model this data |
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Similar structure data | |
EM raw data | EMPIAR-10736 (Title: Cryo-EM of the human insulin receptor ectodomain in complex with an insulin analog with truncated B chain and enlongated A chain Data size: 11.7 TB Data #1: Unaligned multi-frame micrographs (40 e-/A2 dose) [micrographs - multiframe] Data #2: unaligned micrographs (60 e-/A2 dose) [micrographs - multiframe]) |
-Links
-Assembly
Deposited unit |
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-Components
#1: Protein | Mass: 104632.695 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: Homo sapiens (human) References: UniProt: P06213-2, receptor protein-tyrosine kinase #2: Protein/peptide | Mass: 2736.106 Da / Num. of mol.: 3 / Mutation: N21H / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01308 #3: Protein/peptide | Mass: 2537.951 Da / Num. of mol.: 3 / Mutation: H10E, G20L / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01308 Sequence details | Elongated Insulin chain A was modified to contain three additional C-terminal residues (SQL) | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Insulin receptor ectodomain in complex with insulin analog Vh-Ins-HSLQ - asymmetric conformation. Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES | |||||||||
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Molecular weight | Value: 0.209 MDa / Experimental value: NO | |||||||||
Source (natural) | Organism: Homo sapiens (human) | |||||||||
Source (recombinant) | Organism: Homo sapiens (human) | |||||||||
Buffer solution | pH: 8 Details: Equal parts HBS(50 mM HEPES pH 7.5, 150 mM NaCl ) and TBS (25 mM Tris pH 8.5, 150 mM NaCl) | |||||||||
Buffer component |
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Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | |||||||||
Specimen support | Grid type: Quantifoil R1.2/1.3 | |||||||||
Vitrification | Instrument: FEI VITROBOT MARK II / Cryogen name: ETHANE / Humidity: 80 % / Chamber temperature: 277 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.19.1_4122: / Classification: refinement | |||||||||||||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 43457 / Symmetry type: POINT | |||||||||||||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | |||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 200.72 Å2 | |||||||||||||||||||||||||||||||||||
Refine LS restraints |
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