Fluoroketone inhibition of Ca(2+)-independent phospholipase A2 through binding pocket association defined by hydrogen/deuterium exchange and molecular dynamics.
Fluoroketone inhibition of Ca(2+)-independent phospholipase A2 through binding pocket association defined by hydrogen/deuterium exchange and molecular dynamics.
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DOI：
10.1021/ja306490g
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发表时间：
2013-01-30
影响因子：
15
通讯作者：
Dennis EA
中科院分区：
文献类型：
--
作者：
Hsu YH;Bucher D;Cao J;Li S;Yang SW;Kokotos G;Woods VL Jr;McCammon JA;Dennis EA
用氢交换质谱仪(DXMS)和分子动力学(MD)相结合的方法研究了荧光酮(FK)配体通过非钙非依赖性磷脂酶A2(IPLA2)抑制基团的机制。IPLA2的模型是通过与Patatin的已知结构同源建立的，并通过广泛的MD模拟进行平衡。在模拟期间确定了空袋，并研究了它们容纳FK抑制剂的能力。配体对接技术表明，有效的抑制剂1，1，1，3-四氟-7-苯基庚烷-2-酮(PHFK)在活性中心口袋内形成有利的相互作用，阻止磷脂底物进入。极性氟酮头基通过与残基Gly486、Gly487和Ser519的氢键稳定。非极性脂肪链和芳香族基团通过与Met544、Val548、Phe549、Leu560和Ala640的疏水接触而稳定。DXMS实验表明，在阻滞剂的存在下，接触区域的重氢显著减少，支持了这种结合模式。FK配体与iPLA2精确结合模式的发现将极大地提高我们设计具有更高效力和选择性的新抑制剂的能力。
The mechanism of inhibition of group VIA Ca2+-independent phospholipase A2 (iPLA2) by fluoroketone (FK) ligands is examined by a combination of deuterium exchange mass spectrometry (DXMS) and molecular dynamics (MD). Models for iPLA2 were built by homology with the known structure of patatin and equilibrated by extensive MD simulations. Empty pockets were identified during the simulations and studied for their ability to accommodate FK inhibitors. Ligand docking techniques showed that the potent inhibitor 1,1,1,3-tetrafluoro-7-phenylheptan-2-one (PHFK) forms favorable interactions inside an active-site pocket, where it blocks the entrance of phospholipid substrates. The polar fluoroketone headgroup is stabilized by hydrogen bonds with residues Gly486, Gly487, and Ser519. The nonpolar aliphatic chain and aromatic group are stabilized by hydrophobic contacts with Met544, Val548, Phe549, Leu560, and Ala640. The binding mode is supported by DXMS experiments showing an important decrease of deuteration in the contact regions in the presence of the inhibitor. The discovery of the precise binding mode of FK ligands to the iPLA2 should greatly improve our ability to design new inhibitors with higher potency and selectivity.
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影响因子：
4.8
作者：
Gadd, ME;Broekemeier, KM;Pfeiffer, DR
通讯作者：
Pfeiffer, DR
影响因子：
4.8
作者：
Hsu, Yuan-Hao;Burke, John E.;Dennis, Edward A.
通讯作者：
Dennis, Edward A.
影响因子：
4.4
作者：
LEE, WC;SALIDO, E;YEN, PH
通讯作者：
YEN, PH
影响因子：
2.9
作者：
Jacobson, MP;Pincus, DL;Friesner, RA
通讯作者：
Friesner, RA
溴烯醇内酯和三氟甲基酮对巨噬细胞 CA2+-独立磷脂酶 A(2) 的抑制
影响因子：
4.8
作者：
ACKERMANN, EJ;CONDEFRIEBOES, K;DENNIS, EA
通讯作者：
DENNIS, EA