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Biophysical Characterization of Methyl-lysine Reader Proteins

Identification of potent inhibitors

Methyl-lysine binding (reader) proteins recognize various levels of lysine methylation and mediate signaling events that are induced by histone methylation. Therefore, these proteins are referred to as readers of the epigenetic code. Methyl-lysine binders are categorized into three families according to their respective binding domains: The plant homeodomain (PHD) zinc finger proteins, the WD40 repeat domain-containing proteins, and the so called Royal family of reader proteins, including Tudor, chromodomain, Pro-Trp-Trp-Pro (PWWP), and malignant brain tumor (MBT) domain containing proteins. Reader proteins can serve as recruitment proteins for various enzymes, function as linker or auxiliary proteins, act as transcription factors, oncogenic proteins, or tumor suppressors.

There is a growing number of reader proteins that are shown to be involved in disease development and progression. Despite the availability of 3D structural data sets only a few potent and selective inhibitors are reported while mostly only rather weak inhibitors have been found. However, potent inhibitors would help to assess drugability and usability of methyl-lysine readers in drug discovery.

Our approach to address this issues is to apply a broad spectrum of methods ranging from microbiology, molecular biology and protein chemistry to analytical tools such as high throughput screening (HTS), microscale thermophoresis (MST), isothermal calorimetry (ITC), and determination of three dimensional structures using x-ray crystallography.  

Dr. Sheng Wang

Dr. Ling Peng

 

Center for Clinical Research

University Freiburg Medical Center

Breisacherstrasse 66

D-79106 Freiburg i. Br.

Germany

+49 (0)761-270 63350     

 

sheng.wang@uniklinik-freiburg.de