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TitleMechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex.
Journal, issue, pagesCommun Chem, Vol. 7, Issue 1, Page 183, Year 2024
Publish dateAug 16, 2024
AuthorsQi 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 /
PubMed AbstractPTPN2 (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.
External linksCommun Chem / PubMed:39152201 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.93 - 3.3 Å
Structure data

42247

8uh6

EMDB-42247, PDB-8uh6:
Degrader-induced complex between PTPN2 and CRBN-DDB1
Method: EM (single particle) / Resolution: 3.3 Å

PDB-8u0h:
Crystal structure of PTPN2 with a PROTAC
Method: X-RAY DIFFRACTION / Resolution: 1.93 Å

Chemicals


ChemComp, No image

ChemComp-UB0:
Unknown entry

ChemComp-ACT:
ACETATE ION

ChemComp-NA:
Unknown entry

ChemComp-HOH:
WATER


ChemComp, No image

ChemComp-WO8:
Unknown entry

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsHYDROLASE / protein tyrosine phosphatase / degrader / PROTAC

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