STRUCTURE / FUNCTION ANALYSIS OF EUKARYOTIC PROTEIN KINASES AND PHOSPHO-REGUL

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 人类基因组编码超过500种蛋白激酶。这些酶通过催化ATP的γ磷酸转移到靶蛋白中特定的羟基侧链上来调节蛋白质功能。蛋白质磷酸化通过诱导构象变化或促进大分子组装体的形成来影响蛋白质功能。由突变或病毒颠覆机制引起的异常蛋白激酶功能引起细胞功能障碍，这是许多人类疾病的基础。 通过使用小分子治疗剂抵消异常蛋白激酶功能的能力已经验证了蛋白激酶作为可药物化靶点。 蛋白激酶作为细胞生物学调节剂的普遍性源于结构的可塑性，其允许催化转换和底物识别机制的多样化。迄今为止，只有一小部分真核蛋白激酶的结构特征。在我的实验室，我们正在寻求揭示新的催化开关，底物识别和下游磷酸调控机制的结构基础。我们的长期目标是利用我们对蛋白激酶和磷酸调节系统的了解来开发治疗疾病的药物。目前，我的实验室正在对10种不同的蛋白激酶/磷酸调节系统进行X射线晶体学研究。 部分列表包括RNA依赖性蛋白激酶PKR、Chk 2直系同源物Rad 53、波罗家族蛋白激酶、NDR 1激酶调节剂Mob 1、肿瘤抑制因子F-box衔接蛋白Cdc 4和磷酸肌醇结合蛋白激酶Akt。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The human genome encodes just over 500 protein kinases. These enzymes regulate protein function by catalyzing the transfer of the gamma phosphate of ATP onto specific hydroxyl bearing side chains in target proteins. Protein phosphorylation influences protein function either by inducing conformational change or by promoting the formation of macromolecular assemblies. Aberrant protein kinase function arising from mutation or viral subversion mechanisms gives rise to cellular dysfunctions that underlie numerous human diseases. The ability to counteract aberrant protein kinase function through the use of small molecule therapeutics has validated the protein kinase as a drugable target. The pervasiveness of protein kinases as regulators of cellular biology, stems from a plasticity of structure that allows for the diversification of catalytic switching and substrate recognition mechanisms. To date only a small fraction of eukaryotic protein kinases have been structurally characterized. In my lab, we are seeking to uncover the structural basis for novel catalytic switching, substrate recognition and down-stream phospho-regulatory mechanisms. Our long-term goal is to make use of what we learn about protein kinases and phospho-regulatory systems to develop drugs to treat disease. Currently, my lab has x-ray crystallographic studies underway on 10 distinct protein kinase/phospho-regulatory systems. A partial list includes the RNA dependent protein kinase PKR, the Chk2 orthologue Rad53, the polo family protein kinases, the NDR1 kinase regulator Mob1, the tumor suppresor F-box adapter protein Cdc4, and the phospho-inositide binding protein kinase Akt.