Evaluating p97 inhibitor analogues for their domain selectivity and potency against the p97-p47 complex.
Evaluating p97 inhibitor analogues for their domain selectivity and potency against the p97-p47 complex.
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DOI：
10.1002/cmdc.201402420
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发表时间：
2015-01
期刊：
影响因子：
3.4
通讯作者：
Chou, Tsui-Fen
中科院分区：
文献类型：
--
作者：
Fang, Chen-Jie;Gui, Lin;Zhang, Xiaoyi;Moen, Derek R.;Li, Kelin;Frankowski, Kevin J.;Lin, Henry J.;Schoenen, Frank J.;Chou, Tsui-Fen
我们之前发现p97 atp酶抑制剂ML240和ML241特异性靶向野生型p97的d2结构域。此外，p97的主要辅因子之一p47使其效价降低了约50倍。相比之下，DBeQ同时靶向D1和D2结构域，并且对p97-p47复合物的效力仅下降4- 6倍。为了阐明抑制剂的结构-活性关系，我们筛选了200种p97抑制剂类似物，以抑制D1或D2结构域的atp酶活性，或抑制两者的活性，以及对p47效力的影响。其中29种化合物的选择性通过8次滴定进一步检验。四种化合物对D1的atp酶活性有一定的抑制作用。11个化合物对D2的抑制作用较强，4个化合物对D1和D2的抑制作用相似。P47降低了大部分化合物的效价，增加了5种化合物的效价。这些结果强调了开发结构域选择性和复合物特异性p97抑制剂的可能性，以进一步阐明p97及其辅助因子的生理作用。
We previously found that p97 ATPase inhibitors ML240 and ML241 specifically target the D2-domain of wild type p97. In addition, one of the major p97 cofactors, p47, decreases their potencies by ~50-fold. In contrast, DBeQ targets both the D1 and D2 domains and shows only a 4- to 6-fold decrease in potency against the p97-p47 complex. To elucidate structure-activity relationships of inhibitors, we screened 200 p97 inhibitor analogues for the ability to inhibit the ATPase activity of the D1 or D2 domains, or both, as well for effects on p47 potency. The selectivity of 29 of these compounds was further examined by 8-dose titrations. Four compounds showed modest selectivity to inhibit the ATPase activity of D1. Eleven compounds inhibited D2 with greater potencyies, and 4 compounds showed similar potencies against D1 and D2. p47 decreased the potencies of the majority of the compounds and increased the potencies of 5 compounds. These results highlight the possibility of developing domain-selective and complex-specific p97 inhibitors, in order to further elucidate physiological roles of p97 and its cofactors.
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DOI：
10.1074/jbc.m110.215319
发表时间：
2011-05-13
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Chou TF;Deshaies RJ
通讯作者：
Deshaies RJ
影响因子：
64.5
作者：
RABOUILLE, C;LEVINE, TP;WARREN, G
通讯作者：
WARREN, G
影响因子：
5.7
作者：
Davies, Jason M.;Brunger, Axel T.;Weis, William I.
通讯作者：
Weis, William I.
影响因子：
5.6
作者：
Beskow, Anne;Grimberg, Kristian Bjork;Young, Patrick
通讯作者：
Young, Patrick
影响因子：
5.8
作者：
Yeung HO;Förster A;Bebeacua C;Niwa H;Ewens C;McKeown C;Zhang X;Freemont PS
通讯作者：
Freemont PS