Novo Nordisk Fonden - Understanding the biochemical basis for the recognition of crotonyllysine by YEATS domain

Project: Private Foundations

Description

Understanding the molecular complexity of human life remains one the central challenges in biomolecular sciences. Posttranslational modifications of histone proteins have a profound effect on chromatin structure and function, and thus present a hallmark of complexity in the biomolecular world. One of recently discovered modifications is lysine crotonylation that is associated with the active region of human genome. A specific recognition of crotonylated lysine residues by biomedically important YEATS domain proteins takes place in the sandwiched aromatic cage. This project is aimed at unraveling the underlying biochemical origin for the recognition of crotonyllysine byYEATSproteins.Integratedstate-of-the-art experimental andcomputational studies will probe with the highest precision the nature of noncovalent interactions andthe roleofwaterin the biomolecular readout of crotonyllysine. We will examine the importance of tryptophan, tyrosineandphenylalanine residues that constitute the electron-rich aromatic cage of YEATS domains. To probe the proposed energetically favourable π-π-π interactions in biomolecular recognition of crotonyllysine by YEATS domains, the aromatic character of tryptophan residues will be fine-tuned by electron-poorer fluorinated tryptophan residues. In addition, the aromaticity of phenylalanine and tyrosine residues will be systematically tuned by incorporation of the simplest substituted phenylalanine residues, leading to different strengths of π-π-π interactions. We will, for the first time, also explore the chemical space of crotonyllysine analogues, by examining whether its chain length is optimalfor the recognition by YEATS proteins. This work is important because it will advance our basic understanding of the histone code and push the boundaries for molecular and biomedical investigations of histone crotonylation that is associated with development of human diseases, including cancer.
StatusNot started
Effective start/end date01/05/202030/04/2022