Using dynamic combinatorial selection methods to identify chemical modifications of protein function

内在无序区（IDRs）是普遍存在的不采用稳定结构的蛋白质片段，是所有生物体中发现的主要一类蛋白质结构，并且预计存在于大约三分之一的真核蛋白质中。至关重要的是，idr在关键的信号传导和疾病途径中很重要，并且在跨越癌症到蛋白质聚集障碍的过程中占有过多的代表性。该博士研究生将利用化学生物学方法来理解和操纵a-突触核蛋白的聚集行为。a-突触核蛋白是一种内在无序的蛋白质，在神经退行性疾病帕金森病中起着关键作用。我们将应用肽和蛋白质化学、基于片段的配体发现方法、先进的生物物理技术和结构方法的最先进的组合来识别a-synuclein序列的修饰，并系统地绘制其在体外和细胞内聚集行为的后果。研究结果将建立一个识别idr /IDPs调节剂的平台，并为描述聚集机制的新方法打开大门，这是一个至关重要的基本问题，也是推动药物发现的工具。

Intrinsically disordered regions (IDRs), are ubiquitous stretches of protein that do not adopt a stable structure, are a major class of protein structure found in all living organisms, and, are predicted to be present in around a third of eukaryotic proteins. Crucially, IDRs are important and overrepresented in key signalling and disease pathways, spanning cancer to disorders of protein aggregation.This PhD studentship will exploit chemical biology approaches to understand and manipulate the aggregation behaviour of a-synuclein - an intrinsically disordered protein which plays a key role in the neurodegenerative condition: Parkinson's disease. We will apply a state of the art combination of peptide and protein chemistry, fragment based ligand discovery methods and advanced biophysical techniques and structural methods to identify modifications to the sequence of a-synuclein and systematically map the consequences for its aggregation behaviour in vitro and in cells. The results will establish a platform to identify modulators of IDRs/IDPs and open the door to new methods to delineate aggregation mechanisms a basic question of critical importance and tools to drive drug-discovery.