Synergistic effect of conformational changes in phosphoglycerate kinase 1 product release
Synergistic effect of conformational changes in phosphoglycerate kinase 1 product release
复制标题
磷酸甘油酸激酶1产品释放中构象变化的协同效应
DOI：
10.1080/07391102.2022.2152870
复制
发表时间：
2022-12
影响因子：
4.4
通讯作者：
Chu Huiying
中科院分区：
文献类型：
--
作者：
Liu Ye;Li Yan;Wu Sijin;Li Guohui;Chu Huiying
在糖酵解途径中，磷酸甘油酸激酶1 （PGK1）将一个磷酸基从1,3-二磷酸甘油酸（1,3bpg）转移到ADP，生成3-磷酸甘油酸（3PG）和ATP。催化过程伴随着PGK1的开放构象和封闭构象之间的转换。然而，PGK1构象转变与产物释放过程之间的动态协同机制尚不清楚。本文采用分子动力学模拟结合分子力学广义出生表面积（MM/GBSA）分析，证明封闭构象中的PGK1首先释放产物ATP达到半开放构象，然后释放产物3PG达到全开放构象，可以接受新的底物ADP和1,3bpg进入下一个循环。值得注意的是，PGK1在T243位点的磷酸化导致环区（残基L248-E260）在蛋白外翻转，Y324位点的磷酸化导致PGK1变得更松散。这两种修饰都暴露了ADP/ATP结合位点，有利于PGK1的底物/产物结合/释放。此外，其他的翻译后修饰（PTMs）也能够以不同的效果调节配体的结合/释放。我们的研究结果揭示了PGK1构象转变与产物释放的动态协同分子机制，以及PTMs的影响，这将有助于了解PGK1底物/产物转化过程和开发靶向PGK1的小分子药物。由Ramaswamy H. Sarma传达。
Abstract In the glycolysis pathway, phosphoglycerate kinase 1 (PGK1) transfers one phosphoryl-group from 1,3-diphosphoglycerate (1,3BPG) to ADP to product 3-phosphoglycerate (3PG) and ATP. The catalytic process is accompanied with the conversion between the open conformation and the closed conformation of PGK1. However, the dynamic collaboration mechanism between the PGK1 conformation transition and the products releasing process remains poorly understood. Here using molecular dynamics simulations combined with molecular mechanics generalized born surface area (MM/GBSA) analysis, we demonstrated that PGK1 in the closed conformation first releases the product ATP to reach a semi-open conformation, and releases the product 3PG to achieve the full open conformation, which could accept new substrates ADP and 1,3BPG for the next cycle. It is noteworthy that the phosphorylation of PGK1 at T243 causes the loop region (residues L248-E260) flip outside the protein, and the phosphorylation of Y324 leads PGK1 become looser. Both modifications cause the exposure of the ADP/ATP binding site, which was beneficial for the substrates/products binding/releasing of PGK1. In addition, the other post translational modifications (PTMs) were also able to regulate the ligands binding/releasing with different effects. Our results revealed the dynamic cooperative molecular mechanism of PGK1 conformational transition with products releasing, as well as the influence of PTMs, which would contribute to the understanding of PGK1 substrates/products conversion process and the development of small molecule drugs targeting PGK1. Communicated by Ramaswamy H. Sarma.
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