University of Minnesota
University Relations

Minnesota Supercomputing Institute

Log out of MyMSI

Research Abstracts Online
January 2009 - March 2010

Main TOC ....... College TOC ....... Next Abstract

University of Minnesota Twin Cities
Institute of Technology
Department of Chemistry

PI: Mark D. Distefano

Investigations Into Protein Farnesyl Transferase

These researchers have two projects involving protein farnesyl transferase (PFTase), an enzyme involved in post-translational modification of Ras proteins. The inhibition of PFTase prevents tumor cell growth, so PFTase inhibitors can be efficient anti-cancer drugs. Since the enzyme binds transition state (TS) much more tightly than substrate, TS analogs can be the most potent inhibitors. TS analogs can be designed if the structure of the TS in enzymatic reaction is known.

In the first project, the researchers use a model of the TS structure and are analyzing the reactivity of unnatural substrates, which allows for analysis of the flexibility of the enzyme. This knowledge will allow us to refine the structures of the PFTase inhibitors of interest. The results would show the key features of the PFTase catalysis and provide guidelines for TS analogues design.

The second project is an evaluation of PFTase binding for unnatural farnesyl diphosphate analogues. The information gathered from this computational study—in addition to being informative in its own right—will be used in directed evolution experiments. The information obtained will help the directed evolution experiment in that it will assist in limiting the random mutagenesis to just several amino acids, and thereby produce more relevant mutant enzymes.

Group Members

Jonathan Dozier, Graduate Student
Olivier Henry, Research Associate
Kelly Kyro, Graduate Student
Stepan Lenevich, Graduate Student