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- PDB-7md5: Insulin receptor ectodomain dimer complexed with two IRPA-9 parti... -
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Basic information
Entry | Database: PDB / ID: 7md5 | ||||||
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Title | Insulin receptor ectodomain dimer complexed with two IRPA-9 partial agonists | ||||||
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![]() | PEPTIDE BINDING PROTEIN / Insulin receptor | ||||||
Function / homology | ![]() 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 / exocrine pancreas development / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly ...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 / exocrine pancreas development / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly / cargo receptor activity / dendritic spine maintenance / insulin binding / PTB domain binding / negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / adrenal gland development / 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 / activation of protein kinase activity / Insulin processing / neuronal cell body membrane / regulation of protein secretion / amyloid-beta clearance / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / negative regulation of acute inflammatory response / Regulation of gene expression in beta cells / positive regulation of receptor internalization / alpha-beta T cell activation / regulation of embryonic development / regulation of cellular amino acid metabolic process / negative regulation of respiratory burst involved in inflammatory response / insulin receptor substrate binding / transport across blood-brain barrier / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / Synthesis, secretion, and deacylation of Ghrelin / epidermis development / negative regulation of protein secretion / regulation of protein localization to plasma membrane / fatty acid homeostasis / Signal attenuation / negative regulation of lipid catabolic process / negative regulation of gluconeogenesis / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / phosphatidylinositol 3-kinase binding / COPI-mediated anterograde transport / positive regulation of lipid biosynthetic process / heart morphogenesis / negative regulation of reactive oxygen species biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / nitric oxide-cGMP-mediated signaling / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / insulin-like growth factor receptor binding / dendrite membrane / neuron projection maintenance / NPAS4 regulates expression of target genes / positive regulation of protein metabolic process / positive regulation of brown fat cell differentiation / activation of protein kinase B activity / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of glycolytic process / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / receptor-mediated endocytosis / positive regulation of nitric-oxide synthase activity / learning / positive regulation of cytokine production / positive regulation of long-term synaptic potentiation / caveola / acute-phase response / Regulation of insulin secretion / endosome lumen / positive regulation of glucose import / positive regulation of protein secretion / negative regulation of proteolysis / positive regulation of cell differentiation / regulation of transmembrane transporter activity / positive regulation of MAP kinase activity / insulin receptor binding / wound healing / regulation of synaptic plasticity / negative regulation of protein catabolic process / hormone activity / receptor protein-tyrosine kinase / receptor internalization / memory / cognition / cellular response to growth factor stimulus / positive regulation of neuron projection development / positive regulation of protein localization to nucleus / Golgi lumen / peptidyl-tyrosine phosphorylation Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.2 Å | ||||||
![]() | Gomez-Llorente, Y. / Zhou, H. / Scapin, G. | ||||||
![]() | ![]() Title: Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists. Authors: Margaret Wu / Ester Carballo-Jane / Haihong Zhou / Peter Zafian / Ge Dai / Mindy Liu / Julie Lao / Terri Kelly / Dan Shao / Judith Gorski / Dmitri Pissarnitski / Ahmet Kekec / Ying Chen / ...Authors: Margaret Wu / Ester Carballo-Jane / Haihong Zhou / Peter Zafian / Ge Dai / Mindy Liu / Julie Lao / Terri Kelly / Dan Shao / Judith Gorski / Dmitri Pissarnitski / Ahmet Kekec / Ying Chen / Stephen F Previs / Giovanna Scapin / Yacob Gomez-Llorente / Scott A Hollingsworth / Lin Yan / Danqing Feng / Pei Huo / Geoffrey Walford / Mark D Erion / David E Kelley / Songnian Lin / James Mu / ![]() Abstract: Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, ...Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, inherent liabilities (e.g. hypoglycemia) of injectable insulin continue to limit the true therapeutic potential of related agents. Insulin dimers were synthesized to investigate whether partial agonism of the insulin receptor (IR) tyrosine kinase is achievable, and to explore the potential for tissue-selective systemic insulin pharmacology. The insulin dimers induced distinct IR conformational changes compared to native monomeric insulin and substrate phosphorylation assays demonstrated partial agonism. Structurally distinct dimers with differences in conjugation sites and linkers were prepared to deliver desirable IR partial agonist (IRPA). Systemic infusions of a B29-B29 dimer in vivo revealed sharp differences compared to native insulin. Suppression of hepatic glucose production and lipolysis were like that attained with regular insulin, albeit with a distinctly shallower dose-response. In contrast, there was highly attenuated stimulation of glucose uptake into muscle. Mechanistic studies indicated that IRPAs exploit tissue differences in receptor density and have additional distinctions pertaining to drug clearance and distribution. The hepato-adipose selective action of IRPAs is a potentially safer approach for treatment of diabetes. | ||||||
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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PDBx/mmCIF format | ![]() | 295.2 KB | Display | ![]() |
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PDB format | ![]() | 241.6 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 23767MC ![]() 7md4C M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Isoform Short of Insulin ... , 2 types, 4 molecules ABMN
#1: Protein | Mass: 106143.359 Da / Num. of mol.: 2 / Fragment: extracellular domain Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: P06213, receptor protein-tyrosine kinase #2: Protein/peptide | Mass: 3459.836 Da / Num. of mol.: 2 / Fragment: C-terminal helix Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: P06213, receptor protein-tyrosine kinase |
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-Protein/peptide , 2 types, 8 molecules SOQUTPRV
#3: Protein/peptide | Mass: 2383.698 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #4: Protein/peptide | Mass: 3433.953 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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-Sugars , 5 types, 14 molecules ![](data/chem/img/NAG.gif)
#5: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source #6: Polysaccharide | Source method: isolated from a genetically manipulated source #7: Polysaccharide | Source method: isolated from a genetically manipulated source #8: Polysaccharide | Source method: isolated from a genetically manipulated source #9: Sugar | ChemComp-NAG / |
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-Details
Has ligand of interest | N |
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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 |
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Sample preparation
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Molecular weight | Value: 0.23 MDa / Experimental value: YES | ||||||||||||||||||||||||
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Source (recombinant) |
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Buffer solution | pH: 7.4 | ||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Specimen support | Grid material: COPPER / Grid type: Homemade | ||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
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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: ![]() |
Electron lens | Mode: BRIGHT FIELD / Cs: 2.7 mm / Alignment procedure: COMA FREE |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 45 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
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Processing
EM software | Name: Leginon / Category: image acquisition |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
3D reconstruction | Resolution: 5.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 54293 / Symmetry type: POINT |