2M86
Solution structure of Hdm2 with engineered cyclotide
Summary for 2M86
| Entry DOI | 10.2210/pdb2m86/pdb |
| NMR Information | BMRB: 19230 |
| Descriptor | MCo-PMI, E3 ubiquitin-protein ligase Mdm2 (2 entities in total) |
| Functional Keywords | hdm2 oncoprotein, mcoti-i cyclotide, p53 tumor suppressor, protein binding-signaling protein complex, protein binding/signaling protein |
| Biological source | synthetic construct More |
| Cellular location | Nucleus, nucleoplasm: 2M86 |
| Total number of polymer chains | 2 |
| Total formula weight | 19997.72 |
| Authors | Majumder, S.,Ji, Y.,Millard, M.,Borra, R.,Bi, T.,Elnagar, A.Y.,Neamati, N.,Camarero, J.A. (deposition date: 2013-05-07, release date: 2013-07-31, Last modification date: 2024-11-06) |
| Primary citation | Ji, Y.,Majumder, S.,Millard, M.,Borra, R.,Bi, T.,Elnagar, A.Y.,Neamati, N.,Shekhtman, A.,Camarero, J.A. In Vivo Activation of the p53 Tumor Suppressor Pathway by an Engineered Cyclotide. J.Am.Chem.Soc., 135:11623-11633, 2013 Cited by PubMed Abstract: The overexpression of Hdm2 and HdmX is a common mechanism used by many tumor cells to inactive the p53 tumor suppressor pathway promoting cell survival. Targeting Hdm2 and HdmX has emerged as a validated therapeutic strategy for treating cancers with wild-type p53. Small linear peptides mimicking the N-terminal fragment of p53 have been shown to be potent Hdm2/HdmX antagonists. The potential therapeutic use of these peptides, however, is limited by their poor stability and bioavailability. Here, we report the engineering of the cyclotide MCoTI-I to efficiently antagonize intracellular p53 degradation. The resulting cyclotide MCo-PMI was able to bind with low nanomolar affinity to both Hdm2 and HdmX, showed high stability in human serum, and was cytotoxic to wild-type p53 cancer cell lines by activating the p53 tumor suppressor pathway both in vitro and in vivo. These features make the cyclotide MCoTI-I an optimal scaffold for targeting intracellular protein-protein interactions. PubMed: 23848581DOI: 10.1021/ja405108p PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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