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Further understanding of how natural products can interact with proteins on cells

Researchers in the UEA School of Pharmacy have recently published two articles which further our understanding of how natural products can interact with proteins on cells.

The Stokes Lab has investigated how chemicals from the traditional herb, Panax ginseng, can interact with ion channel proteins causing them to be switched on. The research articles were published in Molecular Pharmacology (January 2019) and Scientific Reports (March 2019) and were funded by a BBSRC new investigator project grant to Dr Leanne Stokes.

The first study explains how ginsenosides (the chemicals found within Panax ginseng root) can interact with P2X4 receptors to increase their activity. The team used CRISPR/Cas9 to manipulate P2X receptor expression in brain microglial cells to find out which P2X receptor was targeted by the ginsenosides concluding that P2X7 is the receptor that is enhanced. This study was a global collaborative effort performed by Leanne’s PhD student at RMIT University (Kshitija Dhuna) and a co-supervised PhD student (Matthew Felgate) within the School of Pharmacy building a new collaboration with Dr Julie Sanderson’s team.  

Both studies used a computational method to predict where the chemicals found in ginseng can bind on the receptors of interest (purinergic P2X receptors). This involved the work of Dr Jesus Angulo and his team in the School of Pharmacy in a second new collaboration. Using this computational information the interacting amino acids in the P2X7 receptor were altered using a mutagenesis approach allowing further experimental confirmation of the novel binding site by Dr Stefan Bidula, a post-doc in the Stokes Lab.

Dr Leanne Stokes commented: “This is the first description of a positive allosteric modulator binding pocket on P2X7 receptors. Understanding how we can target this receptor could be useful in developing therapies to enhance the action of this receptor on immune cells which may be a good thing in infectious diseases.”

The research articles can be found here www.nature.com/articles/s41598-019-39771-5 and http://molpharm.aspetjournals.org/content/95/2/210.