From crystal packing to molecular recognition: prediction and discovery of a binding site on the surface of polo-like kinase 1.
From crystal packing to molecular recognition: prediction and discovery of a binding site on the surface of polo-like kinase 1.
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DOI：
10.1002/anie.201008019
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发表时间：
2011-04-18
影响因子：
16.6
通讯作者：
Abell, Chris
中科院分区：
文献类型：
--
作者：
Sledz, Pawel;Stubbs, Christopher J.;Lang, Steffen;Yang, Yong-Qing;McKenzie, Grahame J.;Venkitaraman, Ashok R.;Hyvoenen, Marko;Abell, Chris
众所周知，蛋白质-蛋白质相互作用难以用小分子靶向，因为通常涉及大的不连续表面[1，2]，其可以采用不同的构象与不同的结合伴侣相互作用。[3-5]此外，蛋白质表面是固有柔性的，例如来自高通量筛选的命中报告，发现其结合在先前未识别的由表面柔性产生的口袋中。[6]这些因素显着复杂的蛋白质-蛋白质界面的背景下，基于结构的药物发现。[7]理解蛋白质表面的灵活性并预测其由配体的分子识别调节的适应性变化的能力将为靶向蛋白质-蛋白质相互作用开辟新的途径。然而，尽管有很大的兴趣，但很少有系统的方法来实现这一点。[8，9]晶体结构提供了对蛋白质-蛋白质相互作用基础的分子见解。除了生物学上相关的蛋白质-蛋白质界面之外，相邻分子之间的晶体堆积相互作用存在于晶格中，与溶液中的结构相比，经常引入蛋白质局部区域的变化。[10]虽然在物理性质上相似，但在分子识别的研究中，晶体接触可以与真正的生物相互作用区分开来。[11然而，尽管在非生理溶剂条件和蛋白质浓度下形成，但它们通常诱导蛋白质表面上的构象变化，这可用于提供蛋白质表面的构象变化。
Protein–protein interactions are notoriously difficult to target with small molecules as large, discontinuous surfaces are often involved [1, 2] that can adopt different conformations to interact with diverse binding partners.[3–5] In addition, protein surfaces are inherently flexible, exemplified by reports of hits from high-throughput screens that were found to bind in previously unidentified pockets resulting from surface flexibility.[6] These factors significantly complicate structure-based drug discovery in the context of protein–protein interfaces.[7] The ability to understand the flexibility of the protein surface and predict its adaptive changes conditioned by molecular recognition of a ligand would open up new avenues for targeting protein–protein interactions. However, despite significant interest there are few systematic methods to accomplish this.[8, 9]Crystal structures provide molecular insight into the basis of protein–protein interactions. In addition to biologically relevant protein–protein interfaces, crystal-packing interactions between neighboring molecules are present in the crystal lattice, often introducing changes to local regions of the protein as compared to the structures in solution.[10] Although being similar in their physical nature, crystal contacts can be distinguished from genuine biological interactions in the study of molecular recognition.[11, 12] However, despite forming under non-physiological solvent conditions and protein concentrations, they often induce conformational changes on protein surfaces, which may be used to provide
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影响因子：
3.9
作者：
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DOI：
10.1073/pnas.0401942101
发表时间：
2004-08-03
影响因子：
11.1
作者：
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通讯作者：
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