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- PDB-8uh6: Degrader-induced complex between PTPN2 and CRBN-DDB1 -

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Basic information

Entry
Database: PDB / ID: 8uh6
TitleDegrader-induced complex between PTPN2 and CRBN-DDB1
Components
  • DNA damage-binding protein 1
  • Protein cereblon
  • Tyrosine-protein phosphatase non-receptor type 2
KeywordsHYDROLASE
Function / homology
Function and homology information


negative regulation of interleukin-2-mediated signaling pathway / negative regulation of positive thymic T cell selection / positive regulation of PERK-mediated unfolded protein response / negative regulation of interleukin-4-mediated signaling pathway / negative regulation of platelet-derived growth factor receptor-beta signaling pathway / negative regulation of macrophage colony-stimulating factor signaling pathway / negative regulation of interleukin-6-mediated signaling pathway / regulation of type II interferon-mediated signaling pathway / negative regulation of macrophage differentiation / negative regulation of tyrosine phosphorylation of STAT protein ...negative regulation of interleukin-2-mediated signaling pathway / negative regulation of positive thymic T cell selection / positive regulation of PERK-mediated unfolded protein response / negative regulation of interleukin-4-mediated signaling pathway / negative regulation of platelet-derived growth factor receptor-beta signaling pathway / negative regulation of macrophage colony-stimulating factor signaling pathway / negative regulation of interleukin-6-mediated signaling pathway / regulation of type II interferon-mediated signaling pathway / negative regulation of macrophage differentiation / negative regulation of tyrosine phosphorylation of STAT protein / negative regulation of chemotaxis / negative regulation of monoatomic ion transmembrane transport / positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / negative regulation of receptor signaling pathway via JAK-STAT / positive regulation by virus of viral protein levels in host cell / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / Cul4-RING E3 ubiquitin ligase complex / Interleukin-37 signaling / UV-damage excision repair / syntaxin binding / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding / negative regulation of type I interferon-mediated signaling pathway / Cul4A-RING E3 ubiquitin ligase complex / regulation of hepatocyte growth factor receptor signaling pathway / STAT family protein binding / negative regulation of T cell receptor signaling pathway / insulin receptor recycling / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of type II interferon-mediated signaling pathway / endoplasmic reticulum-Golgi intermediate compartment / negative regulation of reproductive process / negative regulation of developmental process / negative regulation of epidermal growth factor receptor signaling pathway / locomotory exploration behavior / cullin family protein binding / viral release from host cell / peptidyl-tyrosine dephosphorylation / negative regulation of lipid storage / T cell differentiation / positive regulation of Wnt signaling pathway / negative regulation of tumor necrosis factor-mediated signaling pathway / ectopic germ cell programmed cell death / negative regulation of protein-containing complex assembly / Regulation of IFNG signaling / positive regulation of viral genome replication / proteasomal protein catabolic process / protein tyrosine phosphatase activity / positive regulation of gluconeogenesis / protein-tyrosine-phosphatase / protein tyrosine phosphatase activity, metal-dependent / histone H2AXY142 phosphatase activity / non-membrane spanning protein tyrosine phosphatase activity / negative regulation of insulin receptor signaling pathway / B cell differentiation / erythrocyte differentiation / endosome lumen / nucleotide-excision repair / positive regulation of protein-containing complex assembly / Recognition of DNA damage by PCNA-containing replication complex / regulation of circadian rhythm / DNA Damage Recognition in GG-NER / negative regulation of ERK1 and ERK2 cascade / Negative regulation of MET activity / PKR-mediated signaling / receptor tyrosine kinase binding / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / negative regulation of inflammatory response / Wnt signaling pathway / Formation of Incision Complex in GG-NER / Dual incision in TC-NER / positive regulation of protein catabolic process / Gap-filling DNA repair synthesis and ligation in TC-NER / cellular response to UV / rhythmic process / integrin binding / insulin receptor signaling pathway / glucose homeostasis / site of double-strand break / Neddylation / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / transmembrane transporter binding / damaged DNA binding / chromosome, telomeric region / protein ubiquitination / negative regulation of cell population proliferation / DNA repair / apoptotic process / DNA damage response / protein-containing complex binding / negative regulation of apoptotic process / protein kinase binding
Similarity search - Function
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) / RSE1/DDB1/CPSF1 second beta-propeller ...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) / RSE1/DDB1/CPSF1 second beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / : / CPSF A subunit region / RSE1/DDB1/CPSF1 first beta-propeller / Protein-tyrosine phosphatase, non-receptor type-1/2 / : / PUA-like superfamily / Protein tyrosine phosphatase, catalytic domain / PTP type protein phosphatase domain profile. / Protein-tyrosine phosphatase / Tyrosine-specific protein phosphatase, PTPase domain / Protein-tyrosine phosphatase, catalytic / Protein tyrosine phosphatase, catalytic domain motif / Tyrosine specific protein phosphatases active site. / Protein-tyrosine phosphatase, active site / Tyrosine-specific protein phosphatases domain / Tyrosine specific protein phosphatases domain profile. / Protein-tyrosine phosphatase-like / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
: / Tyrosine-protein phosphatase non-receptor type 2 / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsCatalano, C. / Bratkowski, M. / Scapin, G. / Hao, Q.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Commun Chem / Year: 2024
Title: Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex.
Authors: Qi Hao / Manoj K Rathinaswamy / Kelly L Klinge / Matthew Bratkowski / Amirhossein Mafi / Christina K Baumgartner / Keith M Hamel / Gesine K Veits / Rinku Jain / Claudio Catalano / Mark ...Authors: Qi Hao / Manoj K Rathinaswamy / Kelly L Klinge / Matthew Bratkowski / Amirhossein Mafi / Christina K Baumgartner / Keith M Hamel / Gesine K Veits / Rinku Jain / Claudio Catalano / Mark Fitzgerald / Alexander W Hird / Eunice Park / Harit U Vora / James A Henderson / Kenton Longenecker / Charles W Hutchins / Wei Qiu / Giovanna Scapin / Qi Sun / Vincent S Stoll / Chaohong Sun / Ping Li / Dan Eaton / David Stokoe / Stewart L Fisher / Christopher G Nasveschuk / Marcia Paddock / Michael E Kort /
Abstract: PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in ...PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4, and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes.
History
DepositionOct 6, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 11, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: DNA damage-binding protein 1
B: Protein cereblon
C: Tyrosine-protein phosphatase non-receptor type 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)219,1195
Polymers218,0773
Non-polymers1,0422
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 DNA damage-binding protein 1


Mass: 128333.820 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16531
#2: Protein Protein cereblon


Mass: 51777.020 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q96SW2
#3: Protein Tyrosine-protein phosphatase non-receptor type 2 / T-cell protein-tyrosine phosphatase / TCPTP


Mass: 37966.000 Da / Num. of mol.: 1 / Fragment: UNP residues 1-314
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTPN2, PTPT / Production host: Escherichia coli (E. coli) / References: UniProt: P17706, protein-tyrosine-phosphatase
#4: Chemical ChemComp-WO8 / (5P)-3-(carboxymethoxy)-4-chloro-5-(3-{[(4S)-1-({3-[(4-{1-[(3R)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}piperidine-1-carbonyl)amino]phenyl}methanesulfonyl)-2,2-dimethylpiperidin-4-yl]amino}phenyl)thiophene-2-carboxylic acid


Mass: 976.512 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C46H50ClN7O11S2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestY

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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: CRBN-DDB1-PTPN2 complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.21781996 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
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: FEI TITAN 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: 1000 nm
Image recordingElectron dose: 36.09 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 69542 / Symmetry type: POINT

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