The mechanism of pentabromopseudilin inhibition of myosin motor activity
The mechanism of pentabromopseudilin inhibition of myosin motor activity
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DOI：
10.1038/nsmb.1542
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发表时间：
2009-01-01
影响因子：
16.8
通讯作者：
Manstein, Dietmar J.
中科院分区：
文献类型：
--
作者：
Fedorov, Roman;Boehl, Markus;Manstein, Dietmar J.
我们已经确定五溴苯磺地林 (PBP) 是肌球蛋白依赖性过程（例如等长张力发展和无负荷缩短速度）的有效抑制剂。 PBP 诱导的 ATP 结合、ATP 水解和 ADP 解离速率常数的降低延长了在肌动蛋白不存在和存在的情况下每个肌球蛋白 ATP 酶循环所需的时间。此外，在存在抑制剂的情况下，肌动蛋白和核苷酸结合位点之间的偶联会减少。 PBP 的选择性不同于其他肌球蛋白抑制剂。为了阐明 PBP 的结合模式，我们在 Mg2+-ADP-偏钒酸盐和 PBP 存在的情况下结晶了盘基网柄菌 myosin-2 运动结构域。 PBP 的电子密度是明确的，表明 PBP 结合在 50-kDa 结构域尖端附近以前未知的变构位点，距离核苷酸结合位点 16 A，距离肌球蛋白结合袋 7.5 埃。
We have identified pentabromopseudilin (PBP) as a potent inhibitor of myosin-dependent processes such as isometric tension development and unloaded shortening velocity. PBP-induced reductions in the rate constants for ATP binding, ATP hydrolysis and ADP dissociation extend the time required per myosin ATPase cycle in the absence and presence of actin. Additionally, coupling between the actin and nucleotide binding sites is reduced in the presence of the inhibitor. The selectivity of PBP differs from that observed with other myosin inhibitors. To elucidate the binding mode of PBP, we crystallized the Dictyostelium myosin-2 motor domain in the presence of Mg2+-ADP-meta-vanadate and PBP. The electron density for PBP is unambiguous and shows PBP to bind at a previously unknown allosteric site near the tip of the 50-kDa domain, at a distance of 16 A from the nucleotide binding site and 7.5 angstrom away from the blebbistatin binding pocket.