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- PDB-10gh: Cryo-EM structure of Receptor Tyrosine Kinase ROS1 in complex wit... -

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Basic information

Entry
Database: PDB / ID: 10gh
TitleCryo-EM structure of Receptor Tyrosine Kinase ROS1 in complex with Fab-RX5
Components
  • Fab-RX5 heavy chain
  • Fab-RX5 light chain
  • Proto-oncogene tyrosine-protein kinase ROS
KeywordsTRANSFERASE/IMMUNE SYSTEM / Receptor tyrosine kinase / ROS1 extracellular bent-over conformation / Inhibitory Fab-RX5 / 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 speciesMus musculus (house mouse)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.06 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
DepositionJan 19, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 25, 2026Provider: repository / Type: Initial release
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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: Fab-RX5 light chain
C: Fab-RX5 heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)165,51611
Polymers163,1373
Non-polymers2,3798
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: 112553.805 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: Antibody Fab-RX5 light chain


Mass: 25079.678 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Antibody Fab-RX5 heavy chain


Mass: 25503.346 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#5: 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.: 5 / 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 in complex with Fab-RX5 / Type: COMPLEX / Entity ID: #1-#3 / 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
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21.2_5419+SVNmodel refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 166992 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 82.87 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002811978
ELECTRON MICROSCOPYf_angle_d0.494616338
ELECTRON MICROSCOPYf_chiral_restr0.0421844
ELECTRON MICROSCOPYf_plane_restr0.00382061
ELECTRON MICROSCOPYf_dihedral_angle_d4.16561655

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