Molecular dynamics simulations provide insights into ULK-101 potency and selectivity toward autophagic kinases ULK1/2.
Molecular dynamics simulations provide insights into ULK-101 potency and selectivity toward autophagic kinases ULK1/2.
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分子动力学模拟可深入了解 ULK-101 对自噬激酶 ULK1/2 的效力和选择性。
DOI：
10.1101/2023.12.01.569261
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
MacKeigan,JeffreyP
中科院分区：
文献类型：
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作者：
Vaughan,RobertM;Dickson,BradleyM;Martin,KatieR;MacKeigan,JeffreyP
蛋白激酶结构域在序列和结构上都是高度保守的。许多因素，包括磷酸化、氨基酸替换或突变，以及小分子抑制剂结合，都会影响激酶结构域的构象和酶的活性。ULK1和ULK2是丝氨酸/苏氨酸激酶，在自噬中发挥重要作用，自噬是一种细胞内循环过程，能够通过溶酶体降解蛋白质和器官。ULK1/2正在成为人类癌症，特别是KRAS驱动的恶性肿瘤的治疗靶点。在这里，我们对ULK1/2小分子抑制剂ULK-101的假设结合姿态进行了分子动力学(MD)模拟。我们观察到ULK-101与ULK2的三磷酸腺苷(ATP)结合部位的稳定结合状态，通过与铰链骨架和催化赖氨酸侧链的氢键配位。值得注意的是，ULK-101占据了与αC-螺旋的N末端相关的疏水口袋。磷酸结合环(P-loop)的大移动也与ULK-101抑制剂结合和退出ULK2有关。总之，我们的数据支持一个模型来解释ULK-101对ULK1/2的效力。
Kinase domains are highly conserved within proteins in both sequence and structure. Many factors, including phosphorylation, amino acid substitutions or mutations, and small molecule inhibitor binding, influence conformations of the kinase domain and enzymatic activity. ULK1 and ULK2 are serine/threonine kinases that serve important roles in autophagy, an intracellular recycling process capable of degrading proteins and organellesviafusion with lysosomes. ULK1/2 are emerging as therapeutic targets in human cancer, particularly KRAS-driven malignancies. Here, we performed molecular dynamics (MD) simulations to hypothesize bound poses for the ULK1/2 small molecule inhibitor, ULK-101. We observed stable bound states for ULK-101 to the adenosine triphosphate (ATP)-binding site of ULK2, coordinated by hydrogen bonding with the hinge backbone and the catalytic lysine sidechain. Notably, ULK-101 occupies a hydrophobic pocket associated with the N-terminus of the αC-helix. Large movements in the phosphate-binding loop (P-loop) are also associated with ULK-101 inhibitor binding and exit from ULK2. Together, our data support a model to explain ULK-101 potency toward ULK1/2.