A targeted molecular dynamics study of WPD loop movement in PTP1B
A targeted molecular dynamics study of WPD loop movement in PTP1B
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DOI：
10.1016/j.bbrc.2006.04.181
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发表时间：
2006-07-07
影响因子：
3.1
通讯作者：
Boresch, Stefan
中科院分区：
文献类型：
--
作者：
Kamerlin, Shina Caroline Lynn;Rucker, Robert;Boresch, Stefan
靶向分子动力学被用来检查PTP 1B中WPD环闭合的机制。这是酶活性所必需的。鉴定了两个重要区域：R环（残基113-118），其有助于底物结合，以及S环（残基198-209），其经历了似乎对WPD环的运动至关重要的构象变化。S环与α 3-螺旋相邻，其构象变化与α 3-和α 7-螺旋之间相互作用的变化相结合。后一种观察结果与一类新的PTP 1B变构抑制剂有关，特别令人感兴趣[Wiesmann et al.，天然Struc。摩尔11（2004）730-737]。这些化合物通过阻断α 3-螺旋相对于α 7-螺旋的重排来防止WPD环的闭合，迫使酶保持在无催化活性的构象。(c)2006年爱思唯尔公司All rights reserved.
Targeted molecular dynamics was used to examine the mechanism of WPD loop closure in PTP1B. which is essential for the activity of the enzyme. Two important regions are identified: the R-loop (residues 113-118), which assists in substrate binding, and the S-loop (residues 198-209), which undergoes a conformational change that appears to be vital for the movement of the WPD loop. The S-loop is adjacent to the alpha 3-helix, and its conformational change is coupled with a change of interactions between the alpha 3- and alpha 7-helices. This latter observation is of particular interest in connection with a novel class of allosteric inhibitors of PTP1B [Wiesmann et al., Nat. Struc. Mol. Biol. 11 (2004) 730-737]. These compounds prevent the closure of the WPD loop, forcing the enzyme to remain in a catalytically inactive conformation, by blocking the rearrangement of the alpha 3-helix relative to the alpha 7-helix. (c) 2006 Elsevier Inc. All rights reserved.