6DUN

Crystal Structure Analysis of PIN1

6DUN の概要

• エントリーDOI: 10.2210/pdb6dun/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, TRIHYDROXYARSENITE(III) (3 entities in total)
• 機能のキーワード: prolyl isomerase, isomerase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 27462.18

構造登録者

Seo, H.-S.,Dhe-Paganon, S. (登録日: 2018-06-21, 公開日: 2019-03-06, 最終更新日: 2023-10-11)

主引用文献

Kozono, S.,Lin, Y.M.,Seo, H.S.,Pinch, B.,Lian, X.,Qiu, C.,Herbert, M.K.,Chen, C.H.,Tan, L.,Gao, Z.J.,Massefski, W.,Doctor, Z.M.,Jackson, B.P.,Chen, Y.,Dhe-Paganon, S.,Lu, K.P.,Zhou, X.Z.
Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells.
Nat Commun, 9:3069-3069, 2018

PubMed Abstract: Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination safely cures fatal acute promyelocytic leukemia, but their mechanisms of action and efficacy are not fully understood. ATRA inhibits leukemia, breast, and liver cancer by targeting isomerase Pin1, a master regulator of oncogenic signaling networks. Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1's active site. ATRA increases cellular ATO uptake through upregulating aquaporin-9. ATO and ATRA, at clinically safe doses, cooperatively ablate Pin1 to block numerous cancer-driving pathways and inhibit the growth of triple-negative breast cancer cells and tumor-initiating cells in cell and animal models including patient-derived orthotopic xenografts, like Pin1 knockout, which is substantiated by comprehensive protein and microRNA analyses. Thus, synergistic targeting of Pin1 by ATO and ATRA offers an attractive approach to combating breast and other cancers.

PubMed: 30093655
DOI: 10.1038/s41467-018-05402-2

実験手法

X-RAY DIFFRACTION (1.59 Å)