8U0H
Crystal structure of PTPN2 with a PROTAC
Summary for 8U0H
| Entry DOI | 10.2210/pdb8u0h/pdb |
| Descriptor | PTPN2, (5P)-3-(carboxymethoxy)-4-chloro-5-(3-{[(4S)-1-({3-[2-(4-{3-[(3R)-2,6-dioxopiperidin-3-yl]-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl}piperidin-1-yl)acetamido]phenyl}methanesulfonyl)-2,2-dimethylpiperidin-4-yl]amino}phenyl)thiophene-2-carboxylic acid, ACETATE ION, ... (5 entities in total) |
| Functional Keywords | protein tyrosine phosphatase, degrader, protac, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 78028.07 |
| Authors | |
| Primary citation | Hao, Q.,Rathinaswamy, M.K.,Klinge, K.L.,Bratkowski, M.,Mafi, A.,Baumgartner, C.K.,Hamel, K.M.,Veits, G.K.,Jain, R.,Catalano, C.,Fitzgerald, M.,Hird, A.W.,Park, E.,Vora, H.U.,Henderson, J.A.,Longenecker, K.,Hutchins, C.W.,Qiu, W.,Scapin, G.,Sun, Q.,Stoll, V.S.,Sun, C.,Li, P.,Eaton, D.,Stokoe, D.,Fisher, S.L.,Nasveschuk, C.G.,Paddock, M.,Kort, M.E. Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex. Commun Chem, 7:183-183, 2024 Cited by PubMed 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 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. PubMed: 39152201DOI: 10.1038/s42004-024-01263-7 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.93 Å) |
Structure validation
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