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- EMDB-47043: Insulin receptor in complex with both insulin and de novo designe... -

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Basic information

Entry
Database: EMDB / ID: EMD-47043
TitleInsulin receptor in complex with both insulin and de novo designed site-2 binder "S2B".
Map dataCryo-EM map of insulin receptor bound with both insulin and de novo designed site-2 binder called "S2B".
Sample
  • Complex: Insulin receptor bound with both insulin and designed site-2 binder S2B.
    • Protein or peptide: Insulin receptor
    • Protein or peptide: Insulin
    • Protein or peptide: Designed site-2 binder S2B
KeywordsInsulin receptor / insulin / designed binder / SIGNALING PROTEIN
Function / homology
Function and homology information


3-phosphoinositide-dependent protein kinase binding / yolk / Signaling by Insulin receptor / negative regulation of transporter activity / IRS activation / Insulin receptor signalling cascade / Signal attenuation / Insulin receptor recycling / male sex determination / lipoic acid binding ...3-phosphoinositide-dependent protein kinase binding / yolk / Signaling by Insulin receptor / negative regulation of transporter activity / IRS activation / Insulin receptor signalling cascade / Signal attenuation / Insulin receptor recycling / male sex determination / lipoic acid binding / exocrine pancreas development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of glycoprotein biosynthetic process / regulation of hydrogen peroxide metabolic process / regulation of female gonad development / positive regulation of meiotic cell cycle / insulin-like growth factor II binding / positive regulation of developmental growth / nuclear lumen / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly / adrenal gland development / peptidyl-tyrosine autophosphorylation / dendritic spine maintenance / insulin binding / : / cargo receptor activity / negative regulation of glycogen catabolic process / negative regulation of fatty acid metabolic process / Signaling by Insulin receptor / PTB domain binding / IRS activation / Insulin processing / negative regulation of feeding behavior / regulation of protein secretion / positive regulation of peptide hormone secretion / epidermis development / negative regulation of acute inflammatory response / positive regulation of respiratory burst / neuronal cell body membrane / Regulation of gene expression in beta cells / negative regulation of protein phosphorylation / alpha-beta T cell activation / amyloid-beta clearance / heart morphogenesis / positive regulation of receptor internalization / insulin receptor substrate binding / Synthesis, secretion, and deacylation of Ghrelin / response to tumor necrosis factor / positive regulation of phosphorylation / negative regulation of gluconeogenesis / negative regulation of protein secretion / fatty acid homeostasis / positive regulation of brown fat cell differentiation / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / positive regulation of insulin receptor signaling pathway / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / positive regulation of lipid biosynthetic process / negative regulation of respiratory burst involved in inflammatory response / protein kinase activator activity / negative regulation of lipid catabolic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / nitric oxide-cGMP-mediated signaling / regulation of protein localization to plasma membrane / transport vesicle / phosphatidylinositol 3-kinase binding / Insulin receptor recycling / COPI-mediated anterograde transport / positive regulation of nitric-oxide synthase activity / negative regulation of reactive oxygen species biosynthetic process / insulin-like growth factor receptor binding / NPAS4 regulates expression of target genes / animal organ morphogenesis / positive regulation of D-glucose import across plasma membrane / positive regulation of mitotic nuclear division / neuron projection maintenance / male gonad development / peptidyl-tyrosine phosphorylation / endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated endocytosis / positive regulation of glycolytic process / Insulin receptor signalling cascade / regulation of embryonic development / dendrite membrane / endosome lumen / positive regulation of protein secretion / acute-phase response / positive regulation of cytokine production / wound healing / insulin receptor binding / positive regulation of long-term synaptic potentiation / positive regulation of neuron projection development / glucose metabolic process / positive regulation of cell differentiation / negative regulation of protein catabolic process / Regulation of insulin secretion
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 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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 speciesMus musculus (house mouse) / Homo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.1 Å
AuthorsBai XC
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Mol Cell / Year: 2025
Title: Tuning insulin receptor signaling using de novo-designed agonists.
Authors: Xinru Wang / Sarah Cardoso / Kai Cai / Preetham Venkatesh / Albert Hung / Michelle Ng / Catherine Hall / Brian Coventry / David S Lee / Rishabh Chowhan / Stacey Gerben / Jie Li / Weidong An ...Authors: Xinru Wang / Sarah Cardoso / Kai Cai / Preetham Venkatesh / Albert Hung / Michelle Ng / Catherine Hall / Brian Coventry / David S Lee / Rishabh Chowhan / Stacey Gerben / Jie Li / Weidong An / Mara Hon / Michael Gao / Ya-Cheng Liao / Domenico Accili / Eunhee Choi / Xiao-Chen Bai / David Baker /
Abstract: Insulin binding induces conformational changes in the insulin receptor (IR) that activate the intracellular kinase domain and the protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) ...Insulin binding induces conformational changes in the insulin receptor (IR) that activate the intracellular kinase domain and the protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways, regulating metabolism and proliferation. We reasoned that designed agonists inducing different IR conformational changes might induce different downstream responses. We used de novo protein design to generate binders for individual IR extracellular domains and fused them in different orientations with different conformational flexibility. We obtained a series of synthetic IR agonists that elicit a wide range of receptor autophosphorylation, MAPK activation, trafficking, and proliferation responses. We identified designs more potent than insulin, causing longer-lasting glucose lowering in vivo and retaining activity on disease-causing IR mutants, while largely avoiding the cancer cell proliferation induced by insulin. Our findings shed light on how changes in IR conformation and dynamics translate into downstream signaling, and with further development, our synthetic agonists could have therapeutic utility for metabolic and proliferative diseases.
History
DepositionSep 17, 2024-
Header (metadata) releaseOct 1, 2025-
Map releaseOct 1, 2025-
UpdateNov 19, 2025-
Current statusNov 19, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47043.png

Downloads & links

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Map

FileDownload / File: emd_47043.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM map of insulin receptor bound with both insulin and de novo designed site-2 binder called "S2B".
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.88 Å/pix.
x 360 pix.
= 316.8 Å		0.88 Å/pix.
x 360 pix.
= 316.8 Å		0.88 Å/pix.
x 360 pix.
= 316.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.88 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.006
Minimum - Maximum-0.009813555 - 0.031388514
Average (Standard dev.)0.00007342958 (±0.0010008718)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 316.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Cryo-EM map of insulin receptor bound with both...

Fileemd_47043_half_map_1.map
AnnotationCryo-EM map of insulin receptor bound with both insulin and de novo designed site-2 binder called "S2B", half map 2.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Cryo-EM map of insulin receptor bound with both...

Fileemd_47043_half_map_2.map
AnnotationCryo-EM map of insulin receptor bound with both insulin and de novo designed site-2 binder called "S2B", half map 1.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Insulin receptor bound with both insulin and designed site-2 bind...

EntireName: Insulin receptor bound with both insulin and designed site-2 binder S2B.
Components
  • Complex: Insulin receptor bound with both insulin and designed site-2 binder S2B.
    • Protein or peptide: Insulin receptor
    • Protein or peptide: Insulin
    • Protein or peptide: Designed site-2 binder S2B

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Supramolecule #1: Insulin receptor bound with both insulin and designed site-2 bind...

SupramoleculeName: Insulin receptor bound with both insulin and designed site-2 binder S2B.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 400 KDa

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Macromolecule #1: Insulin receptor

MacromoleculeName: Insulin receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 155.790516 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGFGRGCETT AVPLLVAVAA LLVGTAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLL LFRVYGLESL KDLFPNLTVI RGSRLFFNYA LVIFEMVHLK ELGLYNLMNI TRGSVRIEKN NELCYLATID W SRILDSVE ...String:
MGFGRGCETT AVPLLVAVAA LLVGTAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLL LFRVYGLESL KDLFPNLTVI RGSRLFFNYA LVIFEMVHLK ELGLYNLMNI TRGSVRIEKN NELCYLATID W SRILDSVE DNYIVLNKDD NEECGDVCPG TAKGKTNCPA TVINGQFVER CWTHSHCQKV CPTICKSHGC TAEGLCCHKE CL GNCSEPD DPTKCVACRN FYLDGQCVET CPPPYYHFQD WRCVNFSFCQ DLHFKCRNSR KPGCHQYVIH NNKCIPECPS GYT MNSSNL MCTPCLGPCP KVCQILEGEK TIDSVTSAQE LRGCTVINGS LIINIRGGNN LAAELEANLG LIEEISGFLK IRRS YALVS LSFFRKLHLI RGETLEIGNY SFYALDNQNL RQLWDWSKHN LTITQGKLFF HYNPKLCLSE IHKMEEVSGT KGRQE RNDI ALKTNGDQAS CENELLKFSF IRTSFDKILL RWEPYWPPDF RDLLGFMLFY KEAPYQNVTE FDGQDACGSN SWTVVD IDP PQRSNDPKSQ TPSHPGWLMR GLKPWTQYAI FVKTLVTFSD ERRTYGAKSD IIYVQTDATN PSVPLDPISV SNSSSQI IL KWKPPSDPNG NITHYLVYWE RQAEDSELFE LDYCLKGLKL PSRTWSPPFE SDDSQKHNQS EYDDSASECC SCPKTDSQ I LKELEESSFR KTFEDYLHNV VFVPRPSRKR RSLEEVGNVT ATTLTLPDFP NVSSTIVPTS QEEHRPFEKV VNKESLVIS GLRHFTGYRI ELQACNQDSP DERCSVAAYV SARTMPEAKA DDIVGPVTHE IFENNVVHLM WQEPKEPNGL IVLYEVSYRR YGDEELHLC VSRKHFALER GCRLRGLSPG NYSVRVRATS LAGNGSWTEP TYFYVTDYLD VPSNIAKIII GPLIFVFLFS V VIGSIYLF LRKRQPDGPM GPLYASSNPE YLSASDVFPS SVYVPDEWEV PREKITLLRE LGQGSFGMVY EGNAKDIIKG EA ETRVAVK TVNESASLRE RIEFLNEASV MKGFTCHHVV RLLGVVSKGQ PTLVVMELMA HGDLKSHLRS LRPDAENNPG RPP PTLQEM IQMTAEIADG MAYLNAKKFV HRDLAARNCM VAHDFTVKIG DFGMTRDIYE TDYYRKGGKG LLPVRWMSPE SLKD GVFTA SSDMWSFGVV LWEITSLAEQ PYQGLSNEQV LKFVMDGGYL DPPDNCPERL TDLMRMCWQF NPKMRPTFLE IVNLL KDDL HPSFPEVSFF YSEENKAPES EELEMEFEDM ENVPLDRSSH CQREEAGGRE GGSSLSIKRT YDEHIPYTHM NGGKKN GRV LTLPRSNPS

UniProtKB: Insulin receptor

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Macromolecule #2: Insulin

MacromoleculeName: Insulin / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.989862 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MALWMRLLPL LALLALWGPD PAAAFVNQHL CGSHLVEALY LVCGERGFFY TPKTRREAED LQVGQVELGG GPGAGSLQPL ALEGSLQKR GIVEQCCTSI CSLYQLENYC N

UniProtKB: Insulin

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Macromolecule #3: Designed site-2 binder S2B

MacromoleculeName: Designed site-2 binder S2B / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 7.552734 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
SKLEEIEELL KELSKTNPLA KDILWVIEVR TEDGHDPKSE LVFIRQYLKT LNTPEAREIL KIVAP

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm

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Image processing

Particle selectionNumber selected: 977361
CTF correctionSoftware - Name: Gctf / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 6.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 10481
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final 3D classificationSoftware - Name: RELION

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