Engineering the catalytic domain of human protein tyrosine phosphatase β for structure-based drug discovery
Engineering the catalytic domain of human protein tyrosine phosphatase β for structure-based drug discovery
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DOI：
10.1107/s0907444906037784
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发表时间：
2006-12-01
期刊：
影响因子：
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通讯作者：
Peters, Kevin G.
中科院分区：
文献类型：
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作者：
Evdokimov, Artem G.;Pokross, Matthew;Peters, Kevin G.
蛋白酪氨酸磷酸酶（PTPs）在许多生物过程中发挥作用，被认为是药物发现的重要靶点。由于抑制剂的开发具有挑战性，基于晶体结构的设计将有助于提高抑制剂的效力和选择性。蛋白质晶体学在药物发现中的成功应用在很大程度上依赖于感兴趣的蛋白质的高质量晶体结构与药物感兴趣的配体的配合。能够快速地、可重复地制备蛋白质配体晶体是非常重要的。本研究详细介绍了我们为设计人类蛋白酪氨酸磷酸酶β (HPTP β - cd)的催化结构域所做的努力，该结构域具有适合快速周转晶体学的特性。本文首次报道了载脂蛋白HPTP β - cd及其与几种新型小分子抑制剂配合物的结构。
Protein tyrosine phosphatases (PTPs) play roles in many biological processes and are considered to be important targets for drug discovery. As inhibitor development has proven challenging, crystal structure-based design will be very helpful to advance inhibitor potency and selectivity. Successful application of protein crystallography to drug discovery heavily relies on high-quality crystal structures of the protein of interest complexed with pharmaceutically interesting ligands. It is very important to be able to produce protein ligand crystals rapidly and reproducibly for as many ligands as necessary. This study details our efforts to engineer the catalytic domain of human protein tyrosine phosphatase beta (HPTP beta-CD) with properties suitable for rapid-turnaround crystallography. Structures of apo HPTP beta-CD and its complexes with several novel small-molecule inhibitors are presented here for the first time.