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- PDB-9pwq: Cryo-EM structure of receptor tyrosine kinase ROS1 extracellular ... -

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Basic information

Entry
Database: PDB / ID: 9pwq
TitleCryo-EM structure of receptor tyrosine kinase ROS1 extracellular domain in complex with NELL2
Components
  • Protein kinase C-binding protein NELL2
  • Proto-oncogene tyrosine-protein kinase ROS
KeywordsTRANSFERASE/SIGNALING PROTEIN / Receptor tyrosine kinase ROS1 / ROS1-NELL2 complex / TRANSFERASE-SIGNALING PROTEIN complex
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)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.45 Å
AuthorsLi, H. / Klein, D.
Funding support1items
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
DepositionAug 5, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 25, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Mar 4, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Proto-oncogene tyrosine-protein kinase ROS
B: Protein kinase C-binding protein NELL2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)302,33112
Polymers300,1182
Non-polymers2,21210
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Proto-oncogene tyrosine-protein kinase ROS / Proto-oncogene c-Ros / Proto-oncogene c-Ros-1 / Receptor tyrosine kinase c-ros oncogene 1 / c-Ros ...Proto-oncogene c-Ros / Proto-oncogene c-Ros-1 / Receptor tyrosine kinase c-ros oncogene 1 / c-Ros receptor tyrosine kinase


Mass: 207672.344 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Ros1, Ros, Ros-1 / Production host: Homo sapiens (human)
References: UniProt: Q78DX7, receptor protein-tyrosine kinase
#2: Protein Protein kinase C-binding protein NELL2 / NEL-like protein 2 / Nel-related protein 2


Mass: 92446.148 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NELL2, NRP2 / Production host: Homo sapiens (human) / References: UniProt: Q99435
#3: 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.: 10 / 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

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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: Receptor tyrosine kinase ROS1 extracellular domain in complex with NELL2
Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.45 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 59436 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 238.84 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002114420
ELECTRON MICROSCOPYf_angle_d0.553319636
ELECTRON MICROSCOPYf_chiral_restr0.04572195
ELECTRON MICROSCOPYf_plane_restr0.00352484
ELECTRON MICROSCOPYf_dihedral_angle_d4.57251894

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