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- PDB-7mqs: The insulin receptor ectodomain in complex with three venom hybri... -

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Basic information

Entry
Database: PDB / ID: 7mqs
TitleThe insulin receptor ectodomain in complex with three venom hybrid insulin molecules - asymmetric conformation
Components
  • Insulin A chain
  • Insulin B chain
  • Isoform Short of Insulin receptor
KeywordsHORMONE / 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 / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / Signaling by Insulin receptor / negative regulation of feeding behavior / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion ...negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / Signaling by Insulin receptor / negative regulation of feeding behavior / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / Regulation of gene expression in beta cells / negative regulation of acute inflammatory response / positive regulation of protein autophosphorylation / alpha-beta T cell activation / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of respiratory burst involved in inflammatory response / negative regulation of protein secretion / positive regulation of glycogen biosynthetic process / negative regulation of gluconeogenesis / Signal attenuation / fatty acid homeostasis / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / positive regulation of insulin receptor signaling pathway / negative regulation of lipid catabolic process / regulation of protein localization to plasma membrane / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / activation of protein kinase B activity / COPI-mediated anterograde transport / transport vesicle / nitric oxide-cGMP-mediated signaling / negative regulation of reactive oxygen species biosynthetic process / Insulin receptor recycling / insulin-like growth factor receptor binding / positive regulation of brown fat cell differentiation / NPAS4 regulates expression of target genes / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of nitric-oxide synthase activity / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / regulation of transmembrane transporter activity / positive regulation of glycolytic process / positive regulation of long-term synaptic potentiation / endosome lumen / positive regulation of cytokine production / acute-phase response / positive regulation of D-glucose import / positive regulation of protein secretion / positive regulation of cell differentiation / Regulation of insulin secretion / insulin receptor binding / wound healing / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / hormone activity / regulation of synaptic plasticity / positive regulation of neuron projection development / positive regulation of protein localization to nucleus / Golgi lumen / cognition / glucose metabolic process / vasodilation / insulin receptor signaling pathway / glucose homeostasis / cell-cell signaling / regulation of protein localization / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protease binding / positive regulation of cell growth / secretory granule lumen / positive regulation of canonical NF-kappaB signal transduction / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / 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
Insulin / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. / Insulin, conserved site / Insulin family signature. / Insulin-like superfamily
Similarity search - Domain/homology
Insulin / Isoform Short of Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsBlakely, 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 support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: 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
DepositionMay 6, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 16, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 29, 2023Group: Database references / Category: citation / citation_author
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
Revision 1.2Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Structure viewerMolecule:
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Assembly

Deposited unit
E: Isoform Short of Insulin receptor
F: Isoform Short of Insulin receptor
A: Insulin A chain
B: Insulin B chain
C: Insulin A chain
D: Insulin B chain
G: Insulin A chain
H: Insulin B chain


Theoretical massNumber of molelcules
Total (without water)225,0888
Polymers225,0888
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area13350 Å2
ΔGint-83 kcal/mol
Surface area91070 Å2

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Components

#1: Protein Isoform Short of Insulin receptor / IR


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 Insulin A chain


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 Insulin B chain


Mass: 2537.951 Da / Num. of mol.: 3 / Mutation: H10E, G20L / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01308
Has protein modificationY
Sequence detailsElongated Insulin chain A was modified to contain three additional C-terminal residues (SQL)

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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: Insulin receptor ectodomain in complex with insulin analog Vh-Ins-HSLQ - asymmetric conformation.
Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightValue: 0.209 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 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
IDNameBuffer-ID
1HEPES1
2Tris1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK II / Cryogen name: ETHANE / Humidity: 80 % / Chamber temperature: 277 K

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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
Image recordingElectron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.1_4122: / Classification: refinement
EM software
IDNameVersionCategoryDetails
4cryoSPARC2.15CTF correction
7Cootmodel fitting
9PHENIXmodel refinement
10cryoSPARC3.2initial Euler assignment
11cryoSPARC3.2final Euler assignmentNon-uniform refinement
13cryoSPARC3.23D reconstructionNon-uniform refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 43457 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 200.72 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01514356
ELECTRON MICROSCOPYf_angle_d1.71419457
ELECTRON MICROSCOPYf_dihedral_angle_d9.5921899
ELECTRON MICROSCOPYf_chiral_restr0.1022128
ELECTRON MICROSCOPYf_plane_restr0.0112511

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