6LK0

Crystal structure of human wild type TRIP13

6LK0 の概要

• エントリーDOI: 10.2210/pdb6lk0/pdb
• 分子名称: Pachytene checkpoint protein 2 homolog (2 entities in total)
• 機能のキーワード: aaa+ atpase, hexamer helical filament, atp-bound, conformation dynamic, oncoprotein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 48694.72

構造登録者

Wang, Y.,Huang, J.,Li, B.,Xue, H.,Tricot, G.,Hu, L.,Xu, Z.,Sun, X.,Chang, S.,Gao, L.,Tao, Y.,Xu, H.,Xie, Y.,Xiao, W.,Yu, D.,Kong, Y.,Chen, G.,Sun, X.,Lian, F.,Zhang, N.,Wu, X.,Mao, Z.,Zhan, F.,Zhu, W.,Shi, J. (登録日: 2019-12-17, 公開日: 2020-01-22, 最終更新日: 2024-03-27)

主引用文献

Wang, Y.,Huang, J.,Li, B.,Xue, H.,Tricot, G.,Hu, L.,Xu, Z.,Sun, X.,Chang, S.,Gao, L.,Tao, Y.,Xu, H.,Xie, Y.,Xiao, W.,Yu, D.,Kong, Y.,Chen, G.,Sun, X.,Lian, F.,Zhang, N.,Wu, X.,Mao, Z.,Zhan, F.,Zhu, W.,Shi, J.
A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression.
Cancer Res., 80:536-548, 2020

PubMed Abstract: The AAA-ATPase TRIP13 drives multiple myeloma progression. Here, we present the crystal structure of wild-type human TRIP13 at a resolution of 2.6 Å. A small-molecule inhibitor targeting TRIP13 was identified on the basis of the crystal structure. The inhibitor, designated DCZ0415, was confirmed to bind TRIP13 using pull-down, nuclear magnetic resonance spectroscopy, and surface plasmon resonance-binding assays. DCZ0415 induced antimyeloma activity , and in primary cells derived from drug-resistant patients with myeloma. The inhibitor impaired nonhomologous end joining repair and inhibited NF-κB activity. Moreover, combining DCZ0415 with the multiple myeloma chemotherapeutic melphalan or the HDAC inhibitor panobinostat induced synergistic antimyeloma activity. Therefore, targeting TRIP13 may be an effective therapeutic strategy for multiple myeloma, particularly refractory or relapsed multiple myeloma. SIGNIFICANCE: These findings identify TRIP13 as a potentially new therapeutic target in multiple myeloma.

PubMed: 31732653
DOI: 10.1158/0008-5472.CAN-18-3987

実験手法

X-RAY DIFFRACTION (2.6 Å)