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- EMDB-49261: IN-ML-15 bound to IGF1Rzip -

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Basic information

Entry
Database: EMDB / ID: EMD-49261
TitleIN-ML-15 bound to IGF1Rzip
Map datamain map
Sample
  • Complex: IN-ML-15 IGF1Rzip complex
    • Protein or peptide: Insulin-like growth factor 1 receptor
  • Protein or peptide: IN-ML-15 beta
  • Protein or peptide: IN-ML-15 alpha
KeywordsIGF receptor / insulin-like growth factor / insulin / IGF / SIGNALING PROTEIN
Function / homology
Function and homology information


insulin-like growth factor receptor activity / protein kinase complex / insulin-like growth factor binding / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / transcytosis / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly ...insulin-like growth factor receptor activity / protein kinase complex / insulin-like growth factor binding / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / transcytosis / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly / alphav-beta3 integrin-IGF-1-IGF1R complex / peptidyl-tyrosine autophosphorylation / dendritic spine maintenance / regulation of JNK cascade / insulin binding / amyloid-beta clearance / Respiratory syncytial virus (RSV) attachment and entry / insulin receptor substrate binding / SHC-related events triggered by IGF1R / phosphatidylinositol 3-kinase binding / negative regulation of MAPK cascade / insulin-like growth factor receptor signaling pathway / phosphatidylinositol 3-kinase/protein kinase B signal transduction / insulin receptor binding / cellular response to glucose stimulus / receptor protein-tyrosine kinase / insulin receptor signaling pathway / cellular response to amyloid-beta / protein autophosphorylation / positive regulation of cold-induced thermogenesis / protein tyrosine kinase activity / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / signaling receptor complex / Extra-nuclear estrogen signaling / positive regulation of cell migration / immune response / axon / positive regulation of cell population proliferation / negative regulation of apoptotic process / signal transduction / ATP binding / membrane / identical protein binding / plasma membrane
Similarity search - Function
Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / 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 ...Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / 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-like growth factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsKirk NS
Funding support Czech Republic, 2 items
OrganizationGrant numberCountry
Czech Academy of SciencesRVO 61388963 Czech Republic
Czech Science Foundation22-17978S Czech Republic
CitationJournal: Sci Adv / Year: 2026
Title: An engineered insulin analog with dual insulin and IGF-1 receptor agonism and distinct signaling.
Authors: Irena Selicharová / Nicholas S Kirk / Anna Kertisová / Marta Lubos / Katarína Mitrová / Terezie Ticháčková / Lenka Žáková / Martina Chrudinová / Jana Březinová / Karel Harant / ...Authors: Irena Selicharová / Nicholas S Kirk / Anna Kertisová / Marta Lubos / Katarína Mitrová / Terezie Ticháčková / Lenka Žáková / Martina Chrudinová / Jana Březinová / Karel Harant / Jan Voldřich / Miroslav Hájek / Derek M Huffman / Jiří Jiráček /
Abstract: Insulin and insulin-like growth factors (IGF-1 and IGF-2) regulate metabolism, growth, and development via related receptors. In contexts such as brain function or fetal development, coordinated ...Insulin and insulin-like growth factors (IGF-1 and IGF-2) regulate metabolism, growth, and development via related receptors. In contexts such as brain function or fetal development, coordinated signaling by all three hormones is essential. We report the engineering of [GluB10, D-HisB24, GlyB31, TyrB32]-insulin (), an analog with high affinity for IR-A, IR-B, and especially IGF-1R. binds IGF-1R ~1000-fold more strongly than native insulin, approaching IGF-1 levels. Cryo-electron microscopy structures reveal how minimal substitutions in enable effective binding to both IR-A and IGF-1R. In neuronal cells, robustly activates both IR and IGF-1R pathways, promotes survival, and exceeds native ligands in neuroprotective assays. In vivo, regulates glucose effectively in mice and rats. Phosphoproteomic profiling confirms dual pathway activation and identifies targets specific to . These findings demonstrate that rational design of dual-receptor agonists can yield potent, versatile ligands with therapeutic promise in metabolic control, neuroprotection, and regeneration.
History
DepositionFeb 16, 2025-
Header (metadata) releaseFeb 18, 2026-
Map releaseFeb 18, 2026-
UpdateSep 2, 2026-
Current statusSep 2, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_49261.png

Downloads & links

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Map

FileDownload / File: emd_49261.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmain map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 256 pix.
= 265.216 Å		1.04 Å/pix.
x 256 pix.
= 265.216 Å		1.04 Å/pix.
x 256 pix.
= 265.216 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.036 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.00123
Minimum - Maximum-0.0048327763 - 0.008676454
Average (Standard dev.)0.000020383819 (±0.00022392708)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 265.216 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map A, generated using 3D flex refinement in cryoSPARC

Fileemd_49261_half_map_1.map
Annotationhalf map A, generated using 3D flex refinement in cryoSPARC
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map B, generated using 3D flex refinement in cryoSPARC

Fileemd_49261_half_map_2.map
Annotationhalf map B, generated using 3D flex refinement in cryoSPARC
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : IN-ML-15 IGF1Rzip complex

EntireName: IN-ML-15 IGF1Rzip complex
Components
  • Complex: IN-ML-15 IGF1Rzip complex
    • Protein or peptide: Insulin-like growth factor 1 receptor
  • Protein or peptide: IN-ML-15 beta
  • Protein or peptide: IN-ML-15 alpha

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Supramolecule #1: IN-ML-15 IGF1Rzip complex

SupramoleculeName: IN-ML-15 IGF1Rzip complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 250 KDa

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Macromolecule #1: Insulin-like growth factor 1 receptor

MacromoleculeName: Insulin-like growth factor 1 receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 102.295727 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EICGPGIDIR NDYQQLKRLE NCTVIEGYLH ILLISKAEDY RSYRFPKLTV ITEYLLLFRV AGLESLGDLF PNLTVIRGWK LFYNYALVI FEMTNLKDIG LYNLRNITRG AIRIEKNADL CYLSTVDWSL ILDAVSNNYI VGNKPPKECG DLCPGTMEEK P MCEKTTIN ...String:
EICGPGIDIR NDYQQLKRLE NCTVIEGYLH ILLISKAEDY RSYRFPKLTV ITEYLLLFRV AGLESLGDLF PNLTVIRGWK LFYNYALVI FEMTNLKDIG LYNLRNITRG AIRIEKNADL CYLSTVDWSL ILDAVSNNYI VGNKPPKECG DLCPGTMEEK P MCEKTTIN NEYNYRCWTT NRCQKMCPST CGKRACTENN ECCHPECLGS CSAPDNDTAC VACRHYYYAG VCVPACPPNT YR FEGWRCV DRDFCANILS AESSDSEGFV IHDGECMQEC PSGFIRNGSQ SMYCIPCEGP CPKVCEEEKK TKTIDSVTSA QML QGCTIF KGNLLINIRR GNNIASELEN FMGLIEVVTG YVKIRHSHAL VSLSFLKNLR LILGEEQLEG NYSFYVLDNQ NLQQ LWDWD HRNLTIKAGK MYFAFNPKLC VSEIYRMEEV TGTKGRQSKG DINTRNNGER ASCESDVLHF TSTTTSKNRI IITWH RYRP PDYRDLISFT VYYKEAPFKN VTEYDGQDAC GSNSWNMVDV DLPPNKDVEP GILLHGLKPW TQYAVYVKAV TLTMVE NDH IRGAKSEILY IRTNASVPSI PLDVLSASNS SSQLIVKWNP PSLPNGNLSY YIVRWQRQPQ DGYLYRHNYC SKDKIPI RK YADGTIDIEE VTENPKTEVC GGEKGPCCAC PKTEAEKQAE KEEAEYRKVF ENFLHNSIFV PRPERKRRDV MQVANTTM S SRSRNTTAAD TYNITDPEEL ETEYPFFESR VDNKERTVIS NLRPFTLYRI DIHSCNHEAE KLGCSASNFV FARTMPAEG ADDIPGPVTW EPRPENSIFL KWPEPENPNG LILMYEIKYG SQVEDQRECV SRQEYRKYGG AKLNRLNPGN YTARIQATSL SGNGSWTDP VFFYVQA

UniProtKB: Insulin-like growth factor 1 receptor

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Macromolecule #2: IN-ML-15 beta

MacromoleculeName: IN-ML-15 beta / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 3.389814 KDa
SequenceString:
NQHLCGSELV EALYLVCGER G(DHI)FYTPKTGY

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Macromolecule #3: IN-ML-15 alpha

MacromoleculeName: IN-ML-15 alpha / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 2.383698 KDa
SequenceString:
GIVEQCCTSI CSLYQLENYC N

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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: 8
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 4 K

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: Ab initio
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 166000
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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