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- PDB-7mqr: The insulin receptor ectodomain in complex with four venom hybrid... -

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Basic information

Entry
Database: PDB / ID: 7mqr
TitleThe insulin receptor ectodomain in complex with four venom hybrid insulins - symmetric 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


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 / insulin receptor complex / insulin-like growth factor I binding / exocrine pancreas development / positive regulation of protein-containing complex disassembly / dendritic spine maintenance ...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 / insulin receptor complex / insulin-like growth factor I binding / exocrine pancreas development / positive regulation of protein-containing complex disassembly / dendritic spine maintenance / cargo receptor activity / insulin binding / negative regulation of NAD(P)H oxidase activity / neuronal cell body membrane / adrenal gland development / PTB domain binding / 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 / amyloid-beta clearance / Regulation of gene expression in beta cells / negative regulation of acute inflammatory response / positive regulation of protein autophosphorylation / regulation of embryonic development / alpha-beta T cell activation / positive regulation of receptor internalization / protein kinase activator activity / insulin receptor substrate binding / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of respiratory burst involved in inflammatory response / epidermis development / negative regulation of protein secretion / negative regulation of gluconeogenesis / positive regulation of glycogen biosynthetic process / Signal attenuation / fatty acid homeostasis / phosphatidylinositol 3-kinase binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / positive regulation of insulin receptor signaling pathway / negative regulation of lipid catabolic process / transport across blood-brain barrier / regulation of protein localization to plasma membrane / positive regulation of lipid biosynthetic process / heart morphogenesis / 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 / dendrite membrane / NPAS4 regulates expression of target genes / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of MAP kinase activity / positive regulation of nitric-oxide synthase activity / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / receptor-mediated endocytosis / regulation of transmembrane transporter activity / positive regulation of glycolytic process / learning / positive regulation of long-term synaptic potentiation / positive regulation of cytokine production / endosome lumen / 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 / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase
Similarity search - Function
Insulin receptor, trans-membrane domain / Insulin receptor trans-membrane segment / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Insulin / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. ...Insulin receptor, trans-membrane domain / Insulin receptor trans-membrane segment / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / 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 / 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 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. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Insulin / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.1 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 1.2Nov 20, 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
A: Insulin A chain
B: Insulin B chain
E: Isoform Short of Insulin receptor
C: Insulin A chain
D: Insulin B chain
G: Insulin A chain
H: Insulin B chain
I: Insulin A chain
J: Insulin B chain
F: Isoform Short of Insulin receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)234,78630
Polymers230,36210
Non-polymers4,42420
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "C"
d_2ens_1chain "A"
d_1ens_2chain "B"
d_2ens_2chain "D"
d_1ens_3chain "E"
d_2ens_3chain "F"
d_1ens_4chain "G"
d_2ens_4chain "I"
d_1ens_5chain "H"
d_2ens_5chain "J"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1GLYGLNN1 - 24
d_21ens_1GLYGLNA1 - 24
d_11ens_2ASNLEUB1 - 18
d_21ens_2ASNLEUO1 - 18
d_11ens_3HISASPC1 - 823
d_12ens_3NAGNAGD
d_13ens_3NAGNAGE
d_14ens_3NAGNAGF
d_15ens_3NAGNAGG
d_16ens_3NAGNAGH
d_17ens_3NAGNAGI
d_18ens_3NAGNAGJ
d_19ens_3NAGNAGK
d_110ens_3NAGNAGL
d_111ens_3NAGNAGM
d_21ens_3HISASPT1 - 823
d_22ens_3NAGNAGU
d_23ens_3NAGNAGV
d_24ens_3NAGNAGW
d_25ens_3NAGNAGX
d_26ens_3NAGNAGY
d_27ens_3NAGNAGZ
d_28ens_3NAGNAGAA
d_29ens_3NAGNAGBA
d_210ens_3NAGNAGCA
d_211ens_3NAGNAGDA
d_11ens_4GLYGLNP1 - 24
d_21ens_4GLYGLNR1 - 24
d_11ens_5HISLEUQ1 - 16
d_21ens_5HISLEUS1 - 16

NCS ensembles :
ID
ens_1
ens_2
ens_3
ens_4
ens_5

NCS oper:
IDCodeMatrixVector
1given(-0.998540401787, 0.0380024447543, -0.0383781212615), (-0.0379563951579, -0.99927753635, -0.0019280594163), (-0.0384236654354, -0.000468550088208, 0.999261428454)349.824897151, 355.709176071, 6.17764409833
2given(-0.999835847839, -0.00223130543064, 0.0179805075839), (0.0020993112392, -0.999970737013, -0.00735649439448), (0.0179963960064, -0.00731754012837, 0.99981127386)346.86860961, 350.209296127, -2.05483374293
3given(-0.999976069842, 0.000655888100182, -0.00688691172934), (-0.000695227818187, -0.999983448123, 0.00571140430124), (-0.00688305169591, 0.00571605559905, 0.999959974353)350.467073069, 348.657295334, 0.0552004172298
4given(-0.997260814998, -0.0301839092302, 0.0675262800132), (0.0266018230731, -0.998222449642, -0.0533318295119), (0.0690160117511, -0.0513894216107, 0.996291080693)340.435305326, 355.413992791, -2.15731191284
5given(-0.999741706583, 0.0224466801058, 0.00355902679266), (-0.0222487731187, -0.998585135658, 0.0482982291292), (0.0046381261515, 0.0482065700349, 0.998826618784)344.71095002, 343.011555301, -7.849617767

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Components

#1: Protein/peptide
Insulin A chain


Mass: 2736.106 Da / Num. of mol.: 4 / Mutation: N21H / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01308
#2: Protein/peptide
Insulin B chain


Mass: 2537.951 Da / Num. of mol.: 4 / Mutation: H10E, G20L / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01308
#3: 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, receptor protein-tyrosine kinase
#4: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 20 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN
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 - whole ectodomain.
Type: COMPLEX / Entity ID: #1-#3 / 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
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 71601 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 169.89 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00715218
ELECTRON MICROSCOPYf_angle_d1.29220630
ELECTRON MICROSCOPYf_dihedral_angle_d8.5812096
ELECTRON MICROSCOPYf_chiral_restr0.0712320
ELECTRON MICROSCOPYf_plane_restr0.0072632
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AELECTRON MICROSCOPYNCS constraints0.000699266051176
ens_2d_2BELECTRON MICROSCOPYNCS constraints0.000717434231875
ens_3d_2CELECTRON MICROSCOPYNCS constraints0.000709757204019
ens_4d_2DELECTRON MICROSCOPYNCS constraints0.000717029870229
ens_5d_2EELECTRON MICROSCOPYNCS constraints0.000672591286344

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