How do mutations and allosteric inhibitors modulate caspase-7 activity? A molecular dynamics study
How do mutations and allosteric inhibitors modulate caspase-7 activity? A molecular dynamics study
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DOI：
10.1080/07391102.2018.1517611
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发表时间：
2019-09-02
影响因子：
4.4
通讯作者：
Ozbek, Pemra
中科院分区：
文献类型：
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作者：
Bingol, Elif Naz;Sercinoglu, Onur;Ozbek, Pemra
半胱天冬酶是高度调节的半胱氨酸蛋白酶家族的成员，其在细胞凋亡中具有重要作用。药学研究集中在这些分子上，因为它们涉及癌症和神经退行性疾病等疾病。与远离结合位点的二聚体界面结合的小分子通过移动环位置诱导类似于分子的胱天蛋白酶原形式的构象变化。由配体的突变或结合引起的波动机制可以解释该分子功能的关键机制。在这项研究中，我们进行了分子动力学模拟的野生型和突变的结构（C290 N，R187 M，Y223 A，G188 L和G188 P），以及变构抑制结构（DICA结合的caspase-7），以观察单一突变的内在动力学的影响。结果表明，先前已知的突变或变构配体结合后催化活性的变化反映在caspase-7的全局动力学的相应变化中。作者：Ramaswamy H. Sarma
Caspases are members of a highly regulated aspartate-cysteine protease family which have important roles in apoptosis. Pharmaceutical studies focused on these molecules since they are involved in diseases such as cancer and neurodegenerative disorders. A small molecule which binds to the dimeric interface away from the binding site induces a conformational change that resembles the pro-caspase form of the molecule by shifting loop positions. The fluctuation mechanisms caused by mutations or binding of a ligand can explain the key mechanism for the function of that molecule. In this study, we performed molecular dynamics simulations on wild-type and mutated structures (C290N, R187M, Y223A, G188L and G188P) as well as allosterically inhibited structure (DICA-bound caspase-7) to observe the effects of the single mutations on intrinsic dynamics. The results show that previously known changes in catalytic activity upon mutations or allosteric ligand binding are reflected in corresponding changes in the global dynamics of caspase-7. Communicated by Ramaswamy H. Sarma