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- EMDB-72353: Cryo-EM structure of ALK in complex with CRBN/DDB1 and TRI-611 -

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Basic information

Entry
Database: EMDB / ID: EMD-72353
TitleCryo-EM structure of ALK in complex with CRBN/DDB1 and TRI-611
Map data
Sample
  • Complex: Ternary complex of ALK with CRBN/DDB1 and TRI-611
    • Protein or peptide: Protein cereblon
    • Protein or peptide: ALK tyrosine kinase receptor
  • Ligand: ZINC ION
  • Ligand: (3S)-3-{2-oxo-5-[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]-1,3-benzoxazol-3(2H)-yl}piperidine-2,6-dione
KeywordsDNA Binding Protein-Transferase Complex / DNA BINDING PROTEIN / Ternary Complex / Molecular Glue / LIGASE
Function / homology
Function and homology information


ASP-3026-resistant ALK mutants / NVP-TAE684-resistant ALK mutants / alectinib-resistant ALK mutants / brigatinib-resistant ALK mutants / ceritinib-resistant ALK mutants / crizotinib-resistant ALK mutants / lorlatinib-resistant ALK mutants / MDK and PTN in ALK signaling / receptor signaling protein tyrosine kinase activator activity / negative regulation of monoatomic ion transmembrane transport ...ASP-3026-resistant ALK mutants / NVP-TAE684-resistant ALK mutants / alectinib-resistant ALK mutants / brigatinib-resistant ALK mutants / ceritinib-resistant ALK mutants / crizotinib-resistant ALK mutants / lorlatinib-resistant ALK mutants / MDK and PTN in ALK signaling / receptor signaling protein tyrosine kinase activator activity / negative regulation of monoatomic ion transmembrane transport / ALK mutants bind TKIs / phosphorylation / positive regulation of dendrite development / peptidyl-tyrosine autophosphorylation / regulation of neuron differentiation / Signaling by ALK / neuron development / locomotory exploration behavior / energy homeostasis / Cul4A-RING E3 ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex / limb development / negative regulation of lipid catabolic process / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / transmembrane receptor protein tyrosine kinase activity / cell surface receptor protein tyrosine kinase signaling pathway / receptor protein-tyrosine kinase / positive regulation of protein-containing complex assembly / heparin binding / Signaling by ALK fusions and activated point mutants / protein autophosphorylation / regulation of cell population proliferation / protein tyrosine kinase activity / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of apoptotic process / transmembrane transporter binding / signaling receptor complex / protein ubiquitination / perinuclear region of cytoplasm / signal transduction / protein-containing complex / extracellular exosome / ATP binding / membrane / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / ALK/LTK, Glycine-rich domain / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Lon N-terminal domain profile. ...: / ALK/LTK, Glycine-rich domain / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Lon N-terminal domain profile. / Lon protease, N-terminal domain / Lon protease, N-terminal domain superfamily / ATP-dependent protease La (LON) substrate-binding domain / Found in ATP-dependent protease La (LON) / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / LDL receptor-like superfamily / PUA-like 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. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Protein cereblon / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsBart AG / Kamadurai HB
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: Nature / Year: 2026
Title: TRI-611, a selective, brain-penetrant molecular glue degrader of ALK.
Authors: Andrew R Conery / Daniel S La / Artyom A Alekseyenko / David Marcoux / Aaron G Bart / Matt L Harlow / Patrick R Arsenault / Nico R Cantone / Rebecca L Casaubon / Alexander Constan / Hari B ...Authors: Andrew R Conery / Daniel S La / Artyom A Alekseyenko / David Marcoux / Aaron G Bart / Matt L Harlow / Patrick R Arsenault / Nico R Cantone / Rebecca L Casaubon / Alexander Constan / Hari B Kamadurai / Aravind Prasad Medikonda / Duncan E Nunes / Hannah Szeto / Tim J Wigle / Maolin Yu / Aleksandra Zagulyaeva / Christine M Zarate / Lauren Highfield / Nobuyuki Kondo / Aaron N Hata / Kenneth Ngo / Jisu Lee / Prafulla C Gokhale / Caroline Germa / Kathleen I Seyb / Patrick Trojer / Vito J Palombella /
Abstract: Tyrosine kinase inhibitors (TKIs) targeting anaplastic lymphoma kinase (ALK) have transformed the treatment landscape of ALK fusion-positive non-small-cell lung carcinoma (ALK-positive NSCLC), but ...Tyrosine kinase inhibitors (TKIs) targeting anaplastic lymphoma kinase (ALK) have transformed the treatment landscape of ALK fusion-positive non-small-cell lung carcinoma (ALK-positive NSCLC), but the limited options for patients who progress on approved TKIs highlight a continued need for an orthogonal therapeutic approach. TRI-611 is a potent, brain-penetrant molecular glue degrader of ALK fusion proteins with the potential to address this need. TRI-611 promotes the proximity of the ALK kinase domain and CRL4 substrate adaptor CRBN through a unique degron interface distal from the kinase active site. The unique binding interface of TRI-611 leads to selectivity across the proteome including known CRBN neosubstrates and other kinases. TRI-611 treatment induces degradation of all forms of ALK fusion proteins, including wild-type and ALK TKI-resistant versions, leading to regression of cell line and patient-derived subcutaneous and intracranial tumour models of ALK-positive NSCLC. TRI-611 can be combined with orthosteric ALK TKIs, achieving synergistic and durable tumour regressions. TRI-611 represents to our knowledge the first clinical-stage molecular glue degrader targeting an oncogenic gene fusion and has the potential to expand the arsenal of therapeutic options for patients with ALK-positive NSCLC .
History
DepositionAug 27, 2025-
Header (metadata) releaseAug 5, 2026-
Map releaseAug 5, 2026-
UpdateSep 23, 2026-
Current statusSep 23, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72353.png

Downloads & links

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Map

FileDownload / File: emd_72353.map.gz / Format: CCP4 / Size: 669.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.51 Å/pix.
x 560 pix.
= 286.328 Å		0.51 Å/pix.
x 560 pix.
= 286.328 Å		0.51 Å/pix.
x 560 pix.
= 286.328 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.5113 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0025
Minimum - Maximum-0.0063084 - 0.012488743
Average (Standard dev.)-0.000002508862 (±0.0001808789)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions560560560
Spacing560560560
CellA=B=C: 286.328 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_72353_msk_1.map
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AxesZYX

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Histogram (log scale)

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Half map: #2

Fileemd_72353_half_map_1.map
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_72353_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Ternary complex of ALK with CRBN/DDB1 and TRI-611

EntireName: Ternary complex of ALK with CRBN/DDB1 and TRI-611
Components
  • Complex: Ternary complex of ALK with CRBN/DDB1 and TRI-611
    • Protein or peptide: Protein cereblon
    • Protein or peptide: ALK tyrosine kinase receptor
  • Ligand: ZINC ION
  • Ligand: (3S)-3-{2-oxo-5-[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]-1,3-benzoxazol-3(2H)-yl}piperidine-2,6-dione

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Supramolecule #1: Ternary complex of ALK with CRBN/DDB1 and TRI-611

SupramoleculeName: Ternary complex of ALK with CRBN/DDB1 and TRI-611 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein cereblon

MacromoleculeName: Protein cereblon / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.690754 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: SMAGEGDQQD AAHNMGNHLP LLPAESEEED EMEVEDQDSK EAKKPNIINF DTSLPTSHTY LGADMEEFHG RTLHDDDSCQ VIPVLPQVM MILIPGQTLP LQLFHPQEVS MVRNLIQKDR TFAVLAYSNV QEREAQFGTT AEIYAYREEQ DFGIEIVKVK A IGRQRFKV ...String:
SMAGEGDQQD AAHNMGNHLP LLPAESEEED EMEVEDQDSK EAKKPNIINF DTSLPTSHTY LGADMEEFHG RTLHDDDSCQ VIPVLPQVM MILIPGQTLP LQLFHPQEVS MVRNLIQKDR TFAVLAYSNV QEREAQFGTT AEIYAYREEQ DFGIEIVKVK A IGRQRFKV LELRTQSDGI QQAKVQILPE CVLPSTMSAV QLESLNKCQI FPSKPVSRED QCSYKWWQKY QKRKFHCANL TS WPRWLYS LYDAETLMDR IKKQLREWDE NLKDDSLPSN PIDFSYRVAA CLPIDDVLRI QLLKIGSAIQ RLRCELDIMN KCT SLCCKQ CQETEITTKN EIFSLSLCGP MAAYVNPHGY VHETLTVYKA CNLNLIGRPS TEHSWFPGYA WTVAQCKICA SHIG WKFTA TKKDMSPQKF WGLTRSALLP TIPDTEDEIS PDKVILCL

UniProtKB: Protein cereblon

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Macromolecule #2: ALK tyrosine kinase receptor

MacromoleculeName: ALK tyrosine kinase receptor / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.134422 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GPGGSNPNYC FAGKTSSISD LKEVPRKNIT LIRGLGHGAF GEVYEGQVSG MPNDPSPLQV AVKTLPEVCS EQDELDFLME ALIISKFNH QNIVRCIGVS LQSLPRFILL ELMAGGDLKS FLRETRPRPS QPSSLAMLDL LHVARDIACG CQYLEENHFI H RDIAARNC ...String:
GPGGSNPNYC FAGKTSSISD LKEVPRKNIT LIRGLGHGAF GEVYEGQVSG MPNDPSPLQV AVKTLPEVCS EQDELDFLME ALIISKFNH QNIVRCIGVS LQSLPRFILL ELMAGGDLKS FLRETRPRPS QPSSLAMLDL LHVARDIACG CQYLEENHFI H RDIAARNC LLTCPGPGRV AKIGDFGMAR DIYRASYYRK GGCAMLPVKW MPPEAFMEGI FTSKTDTWSF GVLLWEIFSL GY MPYPSKS NQEVLEFVTS GGRMDPPKNC PGPVYRIMTQ CWQHQPEDRP NFAIILERIE YCTQDPDVIN TALPIEYGPL VEE EEK

UniProtKB: ALK tyrosine kinase receptor

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #4: (3S)-3-{2-oxo-5-[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]-1,3-benzo...

MacromoleculeName: (3S)-3-{2-oxo-5-[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]-1,3-benzoxazol-3(2H)-yl}piperidine-2,6-dione
type: ligand / ID: 4 / Number of copies: 1 / Formula: A1CRM
Molecular weightTheoretical: 404.376 Da

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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
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 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: PDB ENTRY
PDB model - PDB ID:

8d7v

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 345494
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

8d7v


Chain - Source name: PDB / Chain - Initial model type: experimental model
Output model

PDB-9xzg:
Cryo-EM structure of ALK in complex with CRBN/DDB1 and TRI-611

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