Exploring the conformational landscape of protein kinases

IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Current opinion in structural biology Pub Date : 2024-07-22 DOI:10.1016/j.sbi.2024.102890
Nancy R. Gough, Charalampos G. Kalodimos
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Abstract

Protein kinases are dynamic enzymes that display complex regulatory mechanisms. Although they possess a structurally conserved catalytic domain, significant conformational dynamics are evident both within a single kinase and across different kinases in the kinome. Here, we highlight methods for exploring this conformational space and its dynamics using kinase domains from ABL1 (Abelson kinase), PKA (protein kinase A), AurA (Aurora A), and PYK2 (proline-rich tyrosine kinase 2) as examples. Such experimental approaches combined with AI-driven methods, such as AlphaFold, will yield discoveries about kinase regulation, the catalytic process, substrate specificity, the effect of disease-associated mutations, as well as new opportunities for structure-based drug design.

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探索蛋白激酶的构象图谱
蛋白激酶是一种动态酶,具有复杂的调控机制。虽然它们拥有结构上一致的催化结构域,但在单个激酶内部以及激酶组中不同激酶之间都存在明显的构象动态变化。在这里,我们以 ABL1(阿贝尔森激酶)、PKA(蛋白激酶 A)、AurA(极光 A)和PYK2(富脯氨酸酪氨酸激酶 2)的激酶结构域为例,重点介绍探索这种构象空间及其动态的方法。这些实验方法与 AlphaFold 等人工智能驱动的方法相结合,将发现激酶调控、催化过程、底物特异性、疾病相关突变的影响以及基于结构的药物设计的新机遇。
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来源期刊
Current opinion in structural biology
Current opinion in structural biology 生物-生化与分子生物学
CiteScore
12.20
自引率
2.90%
发文量
179
审稿时长
6-12 weeks
期刊介绍: Current Opinion in Structural Biology (COSB) aims to stimulate scientifically grounded, interdisciplinary, multi-scale debate and exchange of ideas. It contains polished, concise and timely reviews and opinions, with particular emphasis on those articles published in the past two years. In addition to describing recent trends, the authors are encouraged to give their subjective opinion of the topics discussed. In COSB, we help the reader by providing in a systematic manner: 1. The views of experts on current advances in their field in a clear and readable form. 2. Evaluations of the most interesting papers, annotated by experts, from the great wealth of original publications. [...] The subject of Structural Biology is divided into twelve themed sections, each of which is reviewed once a year. Each issue contains two sections, and the amount of space devoted to each section is related to its importance. -Folding and Binding- Nucleic acids and their protein complexes- Macromolecular Machines- Theory and Simulation- Sequences and Topology- New constructs and expression of proteins- Membranes- Engineering and Design- Carbohydrate-protein interactions and glycosylation- Biophysical and molecular biological methods- Multi-protein assemblies in signalling- Catalysis and Regulation
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