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- EMDB-47324: Cryo-EM Structure of Receptor Tyrosine Kinase ROS1 in Complex wit... -

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Basic information

Entry
Database: EMDB / ID: EMD-47324
TitleCryo-EM Structure of Receptor Tyrosine Kinase ROS1 in Complex with Fab-CT4
Map datacyro-EM map
Sample
  • Complex: Receptor tyrosine kinase ROS1 in complex with Fab-CT4
    • Protein or peptide: Fab-CT4 light chain
    • Protein or peptide: Fab-CT4 heavy chain
    • Protein or peptide: Proto-oncogene tyrosine-protein kinase ROS
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsReceptor tyrosine kinase / ROS1 extracellular bent-over conformation / Inhibitory Fab-CT4 / TRANSFERASE-IMMUNE SYSTEM complex
Function / homology
Function and homology information


columnar/cuboidal epithelial cell development / regulation of phosphate transport / regulation of TOR signaling / regulation of ERK1 and ERK2 cascade / transmembrane receptor protein tyrosine kinase activity / cell surface receptor protein tyrosine kinase signaling pathway / regulation of cell growth / receptor protein-tyrosine kinase / protein tyrosine kinase activity / protein phosphatase binding ...columnar/cuboidal epithelial cell development / regulation of phosphate transport / regulation of TOR signaling / regulation of ERK1 and ERK2 cascade / transmembrane receptor protein tyrosine kinase activity / cell surface receptor protein tyrosine kinase signaling pathway / regulation of cell growth / receptor protein-tyrosine kinase / protein tyrosine kinase activity / protein phosphatase binding / spermatogenesis / gene expression / protein phosphorylation / cell differentiation / signaling receptor complex / negative regulation of gene expression / perinuclear region of cytoplasm / cell surface / signal transduction / ATP binding / plasma membrane
Similarity search - Function
LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / Six-bladed beta-propeller, TolB-like / 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 ...LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / Six-bladed beta-propeller, TolB-like / 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 / 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
Proto-oncogene tyrosine-protein kinase ROS
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.99 Å
AuthorsLi H / Klein D
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2026
Title: Clustering and a conformational switch drive activation of the mammalian receptor tyrosine kinase ROS1.
Authors: Hengyi Li / Jianan Zhang / Tongqing Li / Yueyue Wang / Claudio R Alarcón / Daryl E Klein /
Abstract: Receptor tyrosine kinases (RTKs) are key regulators of cellular signaling and are often co-opted in cancer. ROS1 is an orphan RTK aberrantly expressed in multiple tumors, yet no approved biologic ...Receptor tyrosine kinases (RTKs) are key regulators of cellular signaling and are often co-opted in cancer. ROS1 is an orphan RTK aberrantly expressed in multiple tumors, yet no approved biologic therapies target it, and its activation mechanism remains unknown. Here, we present Cryo-EM structures of mammalian ROS1 in ligand-free and NELL2-bound states, revealing how trimeric NELL2 induces both receptor clustering and a conformational switch that relieves receptor autoinhibition - both mechanisms are required for ROS1 activation. These structures, along with biochemical characterization, reflect a striking evolutionary divergence in regulatory logic compared to the invertebrate ortholog Sevenless (dROS1), highlighting how conserved RTKs can adopt fundamentally different activation strategies. Guided by these structural insights, we develop monoclonal antibodies that either block ligand binding or trap ROS1 in an inactive conformation. These agents potently suppress ROS1 signaling, representing distinct mechanistic classes of biologics that directly target ROS1 activity. Our findings elucidate a distinct mode of RTK regulation and establish a therapeutic framework for cancers driven by ROS1.
History
DepositionOct 15, 2024-
Header (metadata) releaseFeb 25, 2026-
Map releaseFeb 25, 2026-
UpdateMar 4, 2026-
Current statusMar 4, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47324.png

Downloads & links

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Map

FileDownload / File: emd_47324.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcyro-EM map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 480 pix.
= 396. Å		0.83 Å/pix.
x 480 pix.
= 396. Å		0.83 Å/pix.
x 480 pix.
= 396. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.135
Minimum - Maximum-0.6819372 - 1.1693815
Average (Standard dev.)-0.00009604177 (±0.022713184)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 396.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_47324_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: cryo-EM half map A

Fileemd_47324_half_map_1.map
Annotationcryo-EM half map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: cryo-EM half map B

Fileemd_47324_half_map_2.map
Annotationcryo-EM half map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Receptor tyrosine kinase ROS1 in complex with Fab-CT4

EntireName: Receptor tyrosine kinase ROS1 in complex with Fab-CT4
Components
  • Complex: Receptor tyrosine kinase ROS1 in complex with Fab-CT4
    • Protein or peptide: Fab-CT4 light chain
    • Protein or peptide: Fab-CT4 heavy chain
    • Protein or peptide: Proto-oncogene tyrosine-protein kinase ROS
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Receptor tyrosine kinase ROS1 in complex with Fab-CT4

SupramoleculeName: Receptor tyrosine kinase ROS1 in complex with Fab-CT4 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2-#3, #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Proto-oncogene tyrosine-protein kinase ROS

MacromoleculeName: Proto-oncogene tyrosine-protein kinase ROS / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 113.126352 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SLDQSTVLSS CLTSCVTNLG RQLDSGTRYN LSEACIHGCQ FWNSVDQETC ALKCNDTYAT ICERESCEVG CSNAEGSYEE EVLESTELP TAPFASSIGS HGVTLRWNPA NISGVKYIIQ WKYAQLPGSW TFTETVSKLS YTVEPLHPFT EYIFRVVWIF T AQLHLYSP ...String:
SLDQSTVLSS CLTSCVTNLG RQLDSGTRYN LSEACIHGCQ FWNSVDQETC ALKCNDTYAT ICERESCEVG CSNAEGSYEE EVLESTELP TAPFASSIGS HGVTLRWNPA NISGVKYIIQ WKYAQLPGSW TFTETVSKLS YTVEPLHPFT EYIFRVVWIF T AQLHLYSP PSPSYRTHPY GVPETAPLIL NMESWSPDTV EVSWAPPHFP GGPILGYNLR LISKNQKLDS GTQRTSFQFY ST LPNTTYR FSIAAVNEVG EGPEAESTVT TPSPSVQEEE QWLFLSRKTS LRKRSLKYLV DEAHCLWSDA IHHNITGISV YAQ QQVVYF SEGTVIWMKG AANMSDVSDL RIFYQGSGLV SSISIDWLYQ RMYFIMDKLV YVCELKNCSN LEEITPFSLI APQK VVVDS YNGYLFYLLR DGIYRVNLPL PSGRDTKAVR IVESGTLKDF AVKPQSKRII YFNDTMQLFM STFLDGSAFH RVLPW VPLV TVKSFACENN DFLITDGKAI FQQDSLSFNE FIVGCDLSHI EEFGFGNLVI FGSSVQSYPL PGHPQEVSVL FGSREA LIQ WTPPALAIGA SPSAWQNWTY EVKVYSQDIL EITQVFSNIS GTMLNVPELQ SSTKYTVSVR ASSPKGPGPW SAPSVGT TL VPATEPPFIM AVKEDGLWSK PLCSFGPGEF LSSDVGNVSD MDWYNNSLYY SDTKGNVYVR PLNGMDISEN YHIPSIVG A GALAFEWLGH FLYWAGKTYV IQRQSVLTGH TDIVTHVKLL VNDMAVDSVG GYLYWTTLYS VESTRLNGES SLVLQAQPW LSGKKVIALT LDLSDGLLYW LVQDNQCIHL YTAVLRGWSG GDATITEFAA WSTSEISQNA LMYYSGRLFW INGFRIITAQ EIGQRTSVS VSEPAKFNQF TIIQTSLKPL PGNFSSTPKV IPDPVQESSF RIEGHTSSFQ ILWNEPPAVD WGIVFYSVEF S THSKFLII EQQSLPIFTV EGLEPYTLFN LSVTPYTYWG KGQKTSLSFR APE

UniProtKB: Proto-oncogene tyrosine-protein kinase ROS

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Macromolecule #2: Fab-CT4 light chain

MacromoleculeName: Fab-CT4 light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.795408 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: SMASDIQMTQ SPSSLSASVG DRVTITCRAS QSVSSAVAWY QQKPGKAPKL LIYSASSLYS GVPSRFSGSR SGTDFTLTIS SLQPEDFAT YYCQQSYFLI TFGQGTKVEI KRTVAAPSVF IFPPSDSQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS G NSQESVTE ...String:
SMASDIQMTQ SPSSLSASVG DRVTITCRAS QSVSSAVAWY QQKPGKAPKL LIYSASSLYS GVPSRFSGSR SGTDFTLTIS SLQPEDFAT YYCQQSYFLI TFGQGTKVEI KRTVAAPSVF IFPPSDSQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS G NSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGECG GSDYKDDDDK

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Macromolecule #3: Fab-CT4 heavy chain

MacromoleculeName: Fab-CT4 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.58343 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: EISEVQLVES GGGLVQPGGS LRLSCAASGF NIYYYSMHWV RQAPGKGLEW VASISSSYGS TYYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARSWYYSSAI DYWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL ...String:
EISEVQLVES GGGLVQPGGS LRLSCAASGF NIYYYSMHWV RQAPGKGLEW VASISSSYGS TYYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARSWYYSSAI DYWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK KVEPKSCDKT HTSRHHHHHH

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 7 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 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: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.99 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 82174
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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