Divalent metal ion complexes of S100B in the absence and presence of pentamidine
Divalent metal ion complexes of S100B in the absence and presence of pentamidine
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DOI：
10.1016/j.jmb.2008.06.047
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发表时间：
2008-09-26
影响因子：
5.6
通讯作者：
Weber, David J.
中科院分区：
文献类型：
--
作者：
Charpentier, Thomas H.;Wilder, Paul T.;Weber, David J.
作为抑制S100B的一部分，用x射线晶体学分别在2.15埃（R-free = 0.266）和1.85埃（R-free = 0.243）分辨率下测定了载Ca2+和载Zn2+ Ca2+的喷他脒（Pnt）结合的S100B的结构。这些数据与在没有Pnt的情况下解决的x射线结构进行了比较，包括Ca2+负载的S100B和Zn2+ Ca2+负载的S100B（1.88埃；R-free = 0.267）。在Zn2+存在和不存在的情况下，每个S100B亚基对应两个Pnt分子的电子密度被映射为两种药物结合结构。一个Pnt结合位点（位点1）与S100B上的p53肽结合位点（+/- Zn2+）相邻，第二个Pnt分子被映射到二聚体界面（位点2；Zn2+）和S100B上定义Zn2+结合位点的残基附近的一个口袋中。此外，在Ca2+-S100B中加入Zn2+后，S100B的构象发生了变化，与Pnt-Ca2+-S100B相比，Pnt-Zn2+、Ca2+-S100B的1、2位点结合的Pnt的构象和取向发生了变化。Pnt能够适应这种依赖Zn2+的构象变化是出乎意料的，这为该药物抑制S100B提供了一种新的模式。这些数据将有助于开发Ca2+-和Ca2+， Zn2+结合的S100B的新型抑制剂。(C) 2008 Elsevier Ltd版权所有。
As part of an effort to inhibit S100B, structures of pentamidine (Pnt) bound to Ca2+-loaded and Zn2+, Ca2+-loaded S100B were determined by X-ray crystallography at 2.15 angstrom (R-free = 0.266) and 1.85 angstrom (R-free = 0.243) resolution, respectively. These data were compared to X-ray structures solved in the absence of Pnt, including Ca2+-loaded S100B and Zn2+ Ca2+-loaded S100B determined here (1.88 angstrom; R-free = 0.267). In the presence and absence of Zn2+ electron density corresponding to two Pnt molecules per S100B subunit was mapped for both drug-bound structures. One Pnt binding site (site 1) was adjacent to a p53 peptide binding site on S100B (+/- Zn2+), and the second Pnt molecule was mapped to the dimer interface (site 2; Zn2+) and in a pocket near residues that define the Zn2+ binding site on S100B. In addition, a conformational change in S100B was observed upon the addition of Zn2+ to Ca2+-S100B, which changed the conformation and orientation of Pnt bound to sites 1 and 2 of Pnt-Zn2+, Ca2+-S100B when compared to Pnt-Ca2+-S100B. That Pnt can adapt to this Zn2+-dependent conformational change was unexpected and provides a new mode for S100B inhibition by this drug. These data will be useful for developing novel inhibitors of both Ca2+- and Ca2+, Zn2+-bound S100B. (C) 2008 Elsevier Ltd. All rights reserved.