Ph.D.: Tel Aviv University, Israel

Post-doctorate: Massachusetts Institute of Technology, USA

Position: Lecturer, Department of Life Sciences

Faculty of Natural Sciences

E-mail: gure@bgu.ac.il
Webpage:http://cmsprod.bgu.ac.il/Eng/Teva/departments/LifeScience/FacultyMembers/Eyal+Gur.htm

Targeting the bacterial Lon protease – a novel approach for the development of antibiotic compounds

Background

Quality-control systems consisting of ATP-dependent proteases, chaperones, heat-shock proteins, and additional regulatory molecules have evolved to protect cells from the harmful effects of protein unfolding. These networks execute either degradation or refolding of misfolded proteins and assist in the disassembly of protein aggregates. The major enzyme responsible for degrading damaged proteins in bacteria is a hexameric ATP-dependent protease known as Lon. Its importance for proper cellular function is manifested by the phenotypes of lon mutations, which present various physiological defects. In recent years, it has been established that Lon activity is essential for the virulence of many pathogenic bacteria. Therefore, Lon may serve as a potential target for the development of novel anti-bacterial compounds.

Current research

1. The mechanism of protein degradation by Lon (and other ATP-dependent proteases) is complex and involves multiple coordinated steps which act to harvest the energy released from ATP hydrolysis to propel protein degradation in a regulated fashion. The multi-step, complex degradation mechanism employed by Lon offers numerous opportunities to inhibit the protease along the various steps of the substrate processing pathway. Understanding the molecular mechanism of protein degradation by Lon will facilitate the development of various inhibitors of the degradation process. Toward this aim, we use biochemical, genetic and structural approaches to study Lon-mediated proteolysis.
2. Small molecules are defined as non-polymeric organic compounds isolated from natural sources and are often secondary metabolites serving biological functions. The main advantages of using small molecules are several-fold. The vast diversity of these compounds (numbering some hundreds of thousands of different molecules), and the fact that they have evolved to fulfill biological roles result in a very high probability of finding compounds with a desired activity. Moreover, small molecules can reach most compartments of the human body. We have designed a high-throughput screening assay to identify small molecules that can act as selective Lon inhibitors. Identified compounds will be further tested for their qualification as anti-bacterial drugs.
3. Lon is the only ATP-dependent protease known to have a natural protein inhibitor, with E. coli Lon protease being specifically inhibited by the T4-bacteriophage protein, PinA, which seems to inhibit the activity of the Lon ATPase domain. Understanding the inhibition mechanism of Lon by PinA should facilitate future development of novel antibiotic compounds designed to act as specific inhibitors of bacterial Lon proteases.

Selected publications