3A99

Structure of PIM-1 kinase crystallized in the presence of P27KIP1 Carboxy-terminal peptide

3A99 の概要

• エントリーDOI: 10.2210/pdb3a99/pdb
• 分子名称: Proto-oncogene serine/threonine-protein kinase pim-1, MAGNESIUM ION, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (4 entities in total)
• 機能のキーワード: pim-1, p27kip1, peptide drug, prostate cancer, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37013.89

構造登録者

Morishita, D.,Takami, M.,Yoshikawa, S.,Katayama, R.,Sato, S.,Kukimoto-Niino, M.,Umehara, T.,Shirouzu, M.,Sekimizu, K.,Yokoyama, S.,Fujita, N. (登録日: 2009-10-22, 公開日: 2010-11-03, 最終更新日: 2023-11-01)

主引用文献

Morishita, D.,Takami, M.,Yoshikawa, S.,Katayama, R.,Sato, S.,Kukimoto-Niino, M.,Umehara, T.,Shirouzu, M.,Sekimizu, K.,Yokoyama, S.,Fujita, N.
Cell-permeable carboxyl-terminal p27(Kip1) peptide exhibits anti-tumor activity by inhibiting Pim-1 kinase
J.Biol.Chem., 286:2681-2688, 2011

PubMed Abstract: The incidence and death rate of prostate cancer is increasing rapidly. In addition, the low sensitivity of prostate cancer to chemotherapy makes it difficult to treat this condition. The serine/threonine kinase Pim-1 plays an important role in cell cycle progression and apoptosis inhibition, resulting in prostate tumorigenesis. Therefore, Pim-1 inhibition has been expected to be an attractive target for developing new anti-cancer drugs. However, no small compounds targeting Pim-1 have progressed to clinical use because of their lack of specificity. Here, we have reported a new cell-permeable Pim-1 inhibitory p27(Kip1) peptide that could interfere with the binding of Pim-1 to its substrates and act as an anti-cancer drug. The peptide could bind to Pim-1 and inhibit phosphorylation of endogenous p27(Kip1) and Bad by Pim-1. Treatment of prostate cancer with the peptide induces G(1) arrest and subsequently apoptosis in vitro. However, the peptide showed almost no growth inhibitory or apoptosis-inducing effects in normal cells. The peptide could inhibit tumor growth in in vivo prostate cancer xenograft models. Moreover, the peptide treatment could overcome resistance to taxol, one of the first line chemotherapeutic agents for prostate cancer, and a combination of the peptide with taxol synergistically inhibited prostate cancer growth in vivo. These results indicate that a Pim-1 inhibitory p27(Kip1) peptide could be developed as an anti-cancer drug against prostate cancer.

PubMed: 21062737
DOI: 10.1074/jbc.M109.092452

実験手法

X-RAY DIFFRACTION (1.6 Å)