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- EMDB-75142: Cryo-EM structure of receptor tyrosine kinase ROS1 in complex wit... -

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Basic information

Entry
Database: EMDB / ID: EMD-75142
TitleCryo-EM structure of receptor tyrosine kinase ROS1 in complex with NELL2
Map datamap
Sample
  • Complex: Receptor tyrosine kinase ROS1 in complex with NELL2
    • Protein or peptide: Proto-oncogene tyrosine-protein kinase ROS
    • Protein or peptide: Protein kinase C-binding protein NELL2
KeywordsReceptor tyrosine kinase ROS1 / ROS1-NELL2 complex / TRANSFERASE-SIGNALING PROTEIN complex / TRANSFERASE
Function / homology
Function and homology information


columnar/cuboidal epithelial cell development / regulation of phosphate transport / Regulation of commissural axon pathfinding by SLIT and ROBO / regulation of TOR signaling / commissural neuron axon guidance / fertilization / regulation of ERK1 and ERK2 cascade / transmembrane receptor protein tyrosine kinase activity / cell surface receptor protein tyrosine kinase signaling pathway / protein kinase C binding ...columnar/cuboidal epithelial cell development / regulation of phosphate transport / Regulation of commissural axon pathfinding by SLIT and ROBO / regulation of TOR signaling / commissural neuron axon guidance / fertilization / regulation of ERK1 and ERK2 cascade / transmembrane receptor protein tyrosine kinase activity / cell surface receptor protein tyrosine kinase signaling pathway / protein kinase C binding / regulation of cell growth / neuron cellular homeostasis / receptor protein-tyrosine kinase / heparin binding / protein tyrosine kinase activity / protein phosphatase binding / spermatogenesis / gene expression / protein phosphorylation / cell differentiation / signaling receptor complex / negative regulation of gene expression / calcium ion binding / perinuclear region of cytoplasm / cell surface / signal transduction / : / extracellular region / ATP binding / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
: / EGF domain / EGF domain / : / Thrombospondin N-terminal -like domains. / Laminin G domain / von Willebrand factor (vWF) type C domain / von Willebrand factor type C domain / VWFC domain signature. / VWFC domain profile. ...: / EGF domain / EGF domain / : / Thrombospondin N-terminal -like domains. / Laminin G domain / von Willebrand factor (vWF) type C domain / von Willebrand factor type C domain / VWFC domain signature. / VWFC domain profile. / Laminin G domain / Laminin G domain / von Willebrand factor (vWF) type C domain / VWFC domain / LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / : / Calcium-binding EGF domain / Six-bladed beta-propeller, TolB-like / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Epidermal growth factor-like domain. / Fibronectin type III domain / EGF-like domain profile. / Growth factor receptor cysteine-rich domain superfamily / EGF-like domain signature 1. / : / EGF-like domain signature 2. / EGF-like 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 / Concanavalin A-like lectin/glucanase domain superfamily / 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 / Protein kinase C-binding protein NELL2
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.21 Å
AuthorsLi H / Klein D
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
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
DepositionJan 17, 2026-
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_75142.png

Downloads & links

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Map

FileDownload / File: emd_75142.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmap
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 320 pix.
= 264. Å		0.83 Å/pix.
x 320 pix.
= 264. Å		0.83 Å/pix.
x 320 pix.
= 264. 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: 0.119
Minimum - Maximum-1.028424 - 1.5712801
Average (Standard dev.)-0.00004433385 (±0.02299159)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 264.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map A

Fileemd_75142_half_map_1.map
Annotationhalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map B

Fileemd_75142_half_map_2.map
Annotationhalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Receptor tyrosine kinase ROS1 in complex with NELL2

EntireName: Receptor tyrosine kinase ROS1 in complex with NELL2
Components
  • Complex: Receptor tyrosine kinase ROS1 in complex with NELL2
    • Protein or peptide: Proto-oncogene tyrosine-protein kinase ROS
    • Protein or peptide: Protein kinase C-binding protein NELL2

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Supramolecule #1: Receptor tyrosine kinase ROS1 in complex with NELL2

SupramoleculeName: Receptor tyrosine kinase ROS1 in complex with NELL2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)

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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 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Mus musculus (house mouse)
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

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Macromolecule #2: Protein kinase C-binding protein NELL2

MacromoleculeName: Protein kinase C-binding protein NELL2 / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
SequenceString: LGVDPSLQID VLTELELGES TTGVRQVPGL HNGTKAFLFQ DTPRSIKAST ATAEQFFQKL RNKHEFTILV TLKQTHLNSG VILSIHHLD HRYLELESSG HRNEVRLHYR SGSHRPHTEV FPYILADDKW HKLSLAISAS HLILHIDCNK IYERVVEKPS T DLPLGTTF ...String:
LGVDPSLQID VLTELELGES TTGVRQVPGL HNGTKAFLFQ DTPRSIKAST ATAEQFFQKL RNKHEFTILV TLKQTHLNSG VILSIHHLD HRYLELESSG HRNEVRLHYR SGSHRPHTEV FPYILADDKW HKLSLAISAS HLILHIDCNK IYERVVEKPS T DLPLGTTF WLGQRNNAHG YFKGIMQDVQ LLVMPQGFIA QCPDLNRTCP TCNDFHGLVQ KIMELQDILA KTSAKLSRAE QR MNRLDQC YCERTCTMKG TTYREFESWI DGCKNCTCLN GTIQCETLIC PNPDCPLKSA LAYVDGKCCK ECKSICQFQG RTY FEGERN TVYSSSGVCV LYECKDQTMK LVESSGCPAL DCPESHQITL SHSCCKVCKG YDFCSERHNC MENSICRNLN DRAV CSCRD GFRALREDNA YCEDIDECAE GRHYCRENTM CVNTPGSFMC ICKTGYIRID DYSCTEHDEC ITNQHNCDEN ALCFN TVGG HNCVCKPGYT GNGTTCKAFC KDGCRNGGAC IAANVCACPQ GFTGPSCETD IDECSDGFVQ CDSRANCINL PGWYHC ECR DGYHDNGMFS PSGESCEDID ECGTGRHSCA NDTICFNLDG GYDCRCPHGK NCTGDCIHDG KVKHNGQIWV LENDRCS VC SCQNGFVMCR RMVCDCENPT VDLFCCPECD PRLSSQCLHQ NGETLYNSGD TWVQNCQQCR CLQGEVDCWP LPCPDVEC E FSILPENECC PRCVTDPCQA DTIRNDITKT CLDEMNVVRF TGSSWIKHGT ECTLCQCKNG HICCSVDPQC LQELGGGGS IEGRSLDHHH HHHHHHH

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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: 3.21 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 136864
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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