Michael Guo

Michael Guo

Investigating Diversity in Graspeptides


Michael Guo, Garret M. Rubin, Yousong Ding


Dr. Yousong Ding


College of Pharmacy


Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a class of natural products that are attractive candidates for drug discovery, given their functional diversity and macrocyclic stability. RiPPs are defined by their unique biosynthetic pathway where enzyme(s) recognize a leader sequence on the precursor peptide and perform modifications onto the core sequence. This project focuses on graspeptides, a family of RiPPs that utilize ATP-grasp enzymes in this biosynthesis. This family uniquely lacks the β-sheet RiPPs recognition element (RRE) that the majority of other RiPPs systems utilize for enzyme-substrate recognition. Instead, based on structural research, graspeptide leader peptides have an inducible helical structure that binds to the enzyme(s) during biosynthesis. We propose that this helical motif is conserved within all twelve groups of graspeptides and seek to design a leader sequence that would be universally accepted by enzymes from any graspeptide group. This “universal” leader sequence could lead to a new paradigm in RiPPs drug discovery by generating multiple diverse products from the limited set of previously characterized RiPPs biological gene clusters. To begin investigating our hypothesis, bioinformatic tools were used to analyze sequence conservation and protein structure within the twelve groups of graspeptides. Four candidate sequences were then developed based on these observations, each containing the helical motif indicative of the predicted substrate binding site. This early investigation builds knowledge towards developing a successful “universal” leader peptide design as well as informs future biological experimentation.


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Research Pitch

View a 3-minute research pitch below.

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