Structure and Mechanisms of NT5C2 Mutations Driving Thiopurine Resistance in Relapsed Lymphoblastic Leukemia.
Structure and Mechanisms of NT5C2 Mutations Driving Thiopurine Resistance in Relapsed Lymphoblastic Leukemia.
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DOI：
10.1016/j.ccell.2018.06.003
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发表时间：
2018-07-09
期刊：
影响因子：
50.3
通讯作者：
Ferrando AA
中科院分区：
文献类型：
--
作者：
Dieck CL;Tzoneva G;Forouhar F;Carpenter Z;Ambesi-Impiombato A;Sánchez-Martín M;Kirschner-Schwabe R;Lew S;Seetharaman J;Tong L;Ferrando AA
胞质5′-核苷酸酶II基因NT5C2的激活突变驱动急性淋巴细胞白血病对6-巯基嘌呤的耐药。在这里，我们证明了在没有变构激活剂的情况下，组成活性的NT5C2突变K359Q和L375F重新配置了底物进入和催化的催化中心。相反，大多数复发相关突变，包括臂段和沿单体间空腔表面的残基，破坏了负责关闭NT5C2的内置关闭机制。此外，我们发现在Q523X突变中缺失的c端酸性尾可以抑制NT5C2的激活。这些结果揭示了化疗耐药驱动NT5C2突变靶向酶调控的动态机制，对开发NT5C2抑制剂疗法具有重要意义。激活急性淋巴细胞白血病的nt52c突变驱动对6-巯基嘌呤的耐药性。Dieck等人证明有三类突变：最常见的一类破坏了关闭机制，一类将NT5C2锁定在本构活性状态，另一类缺乏c端制动。
Activating mutations in the cytosolic 5’-nucleotidase II gene NT5C2 drive resistance to 6-mercaptopurine in acute lymphoblastic leukemia. Here we demonstrate that constitutively active NT5C2 mutations K359Q and L375F reconfigure the catalytic center for substrate access and catalysis in the absence of allosteric activator. In contrast, most relapse-associated mutations, which involve the arm segment and residues along the surface of the inter-monomeric cavity, disrupt a built-in switch-off mechanism responsible for turning off NT5C2. In addition, we show that the C-terminal acidic tail lost in the Q523X mutation functions to restrain NT5C2 activation. These results uncover dynamic mechanisms of enzyme regulation targeted by chemotherapy resistance-driving NT5C2 mutations, with important implications for the development of NT5C2 inhibitor therapies. Activating NT5C2 mutations in acute lymphoblastic leukemia drive resistance to 6-mercaptopurine. Dieck et al. demonstrate that there are three classes of mutations: the most common ones disrupt the switch-off mechanism, one class locks NT5C2 in the constitutive active state, and one lacks the C-terminal brake.
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影响因子：
46.9
作者：
Heck, Dirk;Kowalczyk, Monika S.;Yudovich, David;Belizaire, Roger;Puram, Rishi V.;McConkey, Marie E.;Thielke, Anne;Aster, Jon C.;Regev, Aviv;Ebert, Benjamin L.
通讯作者：
Ebert, Benjamin L.
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
5
作者：
Brouwer, C;Vogels-Mentink, TM;De Abreu, RA
通讯作者：
De Abreu, RA
用CRISPR/CAS9介导的诱变创建新型蛋白质变体：将筛选副产品变成发现工具。
影响因子：
3.7
作者：
Donovan KF;Hegde M;Sullender M;Vaimberg EW;Johannessen CM;Root DE;Doench JG
通讯作者：
Doench JG