The effects of CapZ peptide (TRTK-12) binding to S100B-Ca2+ as examined by NMR and X-ray crystallography.
The effects of CapZ peptide (TRTK-12) binding to S100B-Ca2+ as examined by NMR and X-ray crystallography.
复制标题
通过 NMR 和 X 射线晶体学检查 CapZ 肽 (TRTK-12) 与 S100B-Ca2+ 结合的影响。
DOI：
10.1016/j.jmb.2009.12.057
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发表时间：
2010-03-12
影响因子：
5.6
通讯作者：
Weber DJ
中科院分区：
文献类型：
--
作者：
Charpentier TH;Thompson LE;Liriano MA;Varney KM;Wilder PT;Pozharski E;Toth EA;Weber DJ
基于结构的药物设计正在进行中，以抑制S100 B-p53相互作用作为治疗恶性黑色素瘤的策略。本文使用X射线晶体学来表征Ca 2 +-S100 B与靶TRTK-12之间的相互作用，所述靶TRTK-12结合S100 B上的p53结合位点。本文测定的Ca 2 +-S100 B（1.5 μ m分辨率）和S100 B-Ca 2 +-TRTK 12（2.0 μ m分辨率）的结构表明，S100 B-Ca 2 +-TRTK 12复合物由TRTK-12的Trp-7与Ca 2 +-S100 B上暴露的疏水结合口袋之间的相互作用主导，所述疏水结合口袋涉及螺旋2和3以及环2中的残基。与S100 B-Ca 2 +-p53肽复合物一样，发现TRTK-12与Ca 2 +-S100 B的结合增加了蛋白质Ca 2+离子结合亲和力。这种效应的一种解释是肽结合引入了结构变化，增加了S100 B的Ca 2+配体的数量和/或改善了S100 B的Ca 2+离子配位几何形状。当比较S100 B-Ca 2 +-TRTK 12和S100 B-Ca 2+的结构时，这种可能性被排除，并且发现蛋白质的钙离子配位在两个EF-手形钙结合结构域中几乎相同（RMSD=0.19）。另一方面，发现Ca 2 +-S100 B的EF 2中残基的B因子随着TRTK-12结合而显著降低。该结果与NMR 15 N弛豫研究一致，该研究表明TRTK-12结合消除了在Ca 2 +-S100 B中观察到的动态特性。这种蛋白质运动的损失也可以解释在结合靶时钙离子结合亲和力如何增加。最后，任何与Ca 2 +-S100 B结合的小分子抑制剂也必须引起钙离子结合亲和力的增加，才能在细胞内有效治疗，因此在未来涉及S100 B的药物设计研究中需要考虑这些数据。
Structure-based drug design is underway to inhibit the S100B-p53 interaction as a strategy for treating malignant melanoma. X-ray crystallography was used here to characterize an interaction between Ca2+-S100B and a target, TRTK-12, which binds to the p53 binding site on S100B. The structures of Ca2+-S100B (1.5 Å resolution) and S100B-Ca2+-TRTK12 (2.0 Å resolution) determined here indicate that the S100B-Ca2+-TRTK12 complex is dominated by an interaction between Trp-7 of TRTK-12 and a hydrophobic binding pocket exposed on Ca2+-S100B involving residues in helices 2 & 3 and loop 2. As with a S100B-Ca2+-p53 peptide complex, TRTK-12 binding to Ca2+-S100B was found to increase the proteins Ca2+ ion binding affinity. One explanation for this effect was that peptide binding introduced a structural change that increased the number of Ca2+ ligands and/or improved Ca2+ ion coordination geometry of S100B. This possibility was ruled out when the structures of S100B-Ca2+-TRTK12 and S100B-Ca2+ were compared and calcium ion coordination by the protein was found to be nearly identical in both EF-hand calcium-binding domains (RMSD=0.19). On the other hand, B-factors for residues in EF2 of Ca2+-S100B were found to be significantly lowered with TRTK-12 bound. This result is consistent with NMR 15N relaxation studies that showed that TRTK-12 binding eliminated dynamic properties observed in Ca2+-S100B. Such a loss of protein motion may also provide an explanation for how calcium ion binding affinity is increased upon binding a target. Lastly, it follows that any small molecule inhibitor bound to Ca2+-S100B would also have to cause an increase in calcium ion binding affinity to be effective therapeutically inside a cell, so these data need to be considered in future drug-design studies involving S100B.
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影响因子：
2.9
作者：
Drohat, AC;Baldisseri, DM;Weber, DJ
通讯作者：
Weber, DJ
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
8
作者：
Drohat, AC;Nenortas, E;Weber, DJ
通讯作者：
Weber, DJ
影响因子：
4.8
作者：
Lin, J;Yang, QY;Weber, DJ
通讯作者：
Weber, DJ
影响因子：
2.7
作者：
DELAGLIO, F;GRZESIEK, S;BAX, A
通讯作者：
BAX, A