Allosteric inhibitor remotely modulates the conformation of the orthestric pockets in mutant IDH2/R140Q.
Allosteric inhibitor remotely modulates the conformation of the orthestric pockets in mutant IDH2/R140Q.
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变构抑制剂远程调节突变体 IDH2/R140Q 中矫形袋的构象
DOI：
10.1038/s41598-017-16427-w
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发表时间：
2017-11-28
影响因子：
4.6
通讯作者：
Cao P
中科院分区：
文献类型：
--
作者：
Chen J;Yang J;Sun X;Wang Z;Cheng X;Lu W;Cai X;Hu C;Shen X;Cao P
代谢酶异柠檬酸脱氢酶2（IDH 2）中的新变体突变R140 Q被发现是癌症中的驱动突变。近年来研究发现，变构抑制剂可选择性抑制IDH 2/R140 Q，并诱导TF-1红白血病和原代人AML细胞分化。然而，其变构抑制机制尚不十分清楚。在这里，我们报告了计算研究的结果，即AGI-6780与同源二聚体界面处的二价阳离子结合螺旋紧密结合，并阻止IDH 2/R140 Q同源二聚体转变为催化所需的闭合构象，导致NADPH的结合自由能降低。如果去除变构抑制剂，IDH 2/R140 Q的原始开放催化中心将逐渐重组为准封闭构象，酶活性可能恢复。与IDH 2/R140 Q不同，AGI-6780将野生型IDH 2的一个单体锁定在无活性的开放构象中，另一个锁定在半封闭构象中，这可以用来解释AGI-6780的选择性。我们的研究结果表明，构象变化的变构抑制剂的抑制效力的主要贡献者。我们的研究也将有助于了解AG-221（一种有前途的变构抑制剂，已被FDA批准）对突变IDH 2的抑制和选择性机制。
Neomorphic mutation R140Q in the metabolic enzyme isocitrate dehydrogenase 2 (IDH2) is found to be a driver mutation in cancers. Recent studies revealed that allosteric inhibitors could selectively inhibit IDH2/R140Q and induce differentiation of TF-1 erythroleukemia and primary human AML cells. However, the allosteric inhibition mechanism is not very clear. Here, we report the results from computational studies that AGI-6780 binds tightly with the divalent cation binding helices at the homodimer interface and prevents the transition of IDH2/R140Q homodimer to a closed conformation that is required for catalysis, resulting in the decrease of the binding free energy of NADPHs. If the allosteric inhibitor is removed, the original open catalytic center of IDH2/R140Q will gradually reorganize to a quasi-closed conformation and the enzymatic activity might recover. Unlike IDH2/R140Q, AGI-6780 locks one monomer of the wild-type IDH2 in an inactive open conformation and the other in a half-closed conformation, which can be used to explain the selectivity of AGI-6780. Our results suggest that conformational changes are the primary contributors to the inhibitory potency of the allosteric inhibitor. Our study will also facilitate the understanding of the inhibitory and selective mechanisms of AG-221 (a promising allosteric inhibitor that has been approved by FDA) for mutant IDH2.
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新的IDH1突变抑制剂治疗急性髓样白血病。
影响因子：
14.8
作者：
Okoye-Okafor, Ujunwa C.;Bartholdy, Boris;Cartier, Jessy;Gao, Enoch N.;Pietrak, Beth;Rendina, Alan R.;Rominger, Cynthia;Quinn, Chad;Smallwood, Angela;Wiggall, Kenneth J.;Reif, Alexander J.;Schmidt, Stanley J.;Qi, Hongwei;Zhao, Huizhen;Joberty, Gerard;Faelth-Savitski, Maria;Bantscheff, Marcus;Drewes, Gerard;Duraiswami, Chaya;Brady, Pat;Groy, Arthur;Narayanagari, Swathi-Rao;Antony-Debre, Ileana;Mitchell, Kelly;Wang, Heng Rui;Kao, Yun-Ruei;Christopeit, Maximilian;Carvajal, Luis;Barreyro, Laura;Paietta, Elisabeth;Makishima, Hideki;Will, Britta;Concha, Nestor;Adams, Nicholas D.;Schwartz, Benjamin;McCabe, Michael T.;Maciejewski, Jaroslav;Verma, Amit;Steidl, Ulrich
通讯作者：
Steidl, Ulrich
影响因子：
11.4
作者：
Medeiros BC;Fathi AT;DiNardo CD;Pollyea DA;Chan SM;Swords R
通讯作者：
Swords R
影响因子：
29
作者：
Pavlova NN;Thompson CB
通讯作者：
Thompson CB
影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
4.8
作者：
Kao, Hsiao-Wen;Liang, Der-Cherng;Wu, Jin-Hou;Kuo, Ming-Chung;Wang, Po-Nan;Yang, Chao-Ping;Shih, Yu-Shu;Lin, Tung-Huei;Huang, Yu-Hui;Shih, Lee-Yung
通讯作者：
Shih, Lee-Yung