2M86

Solution structure of Hdm2 with engineered cyclotide

2M86 の概要

• エントリーDOI: 10.2210/pdb2m86/pdb
• NMR情報: BMRB: 19230
• 分子名称: MCo-PMI, E3 ubiquitin-protein ligase Mdm2 (2 entities in total)
• 機能のキーワード: hdm2 oncoprotein, mcoti-i cyclotide, p53 tumor suppressor, protein binding-signaling protein complex, protein binding/signaling protein
• 由来する生物種: synthetic construct; 詳細
• 細胞内の位置: Nucleus, nucleoplasm: 2M86
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 19997.72

構造登録者

Majumder, S.,Ji, Y.,Millard, M.,Borra, R.,Bi, T.,Elnagar, A.Y.,Neamati, N.,Camarero, J.A. (登録日: 2013-05-07, 公開日: 2013-07-31, 最終更新日: 2024-11-06)

主引用文献

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

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: 23848581
DOI: 10.1021/ja405108p

実験手法

SOLUTION NMR