Many human diseases are linked to the dysfunction of transport proteins and are potential drug targets. Understanding the mechanisms of these proteins in great detail is paramount to designing rational approaches at manipulating their functions using novel therapeutic agents. A critical piece of information is the knowledge of the three-dimensional structures at high resolution. Locher uses X-ray crystallography to determine the structures of transport proteins.
In 2002, he reported the X-ray structure of the first ATP-binding cassette (ABC) transporter while working with Douglas Rees at Caltech, Pasadena USA (Locher et al., Science 296, p. 1091).
In 2003, he joined ETH Zurich as Assistant Professor and was promoted to Associate Professor in 2008. His research focus continues to be the structural and mechanistic investigation of membrane transport proteins. These ubiquitous proteins facilitate the uptake of nutrients, the extrusion of drugs and other toxic substances, and the flipping of lipids. In 2006, Locher reported the structure of the first multi-drug type ABC exporter (Dawson & Locher, Nature 443, p. 180). For this work and follow-up studies, he was awarded the 2007 FEBS Letters Young Investigator Award.
The emphasis of Locher’s research is ABC transporters, a family of integral membrane proteins that catalyze unidirectional substrate transport coupled to the hydrolysis of adenosine triphosphate (ATP). In humans, ABC proteins are associated with several diseases including cystic fibrosis or Tangier disease, and are notorious for their role in causing multidrug resistance of cancer cells. In bacteria, ABC transporters catalyze nutrient uptake or drug extrusion and thus contribute to drug resistance of microbial pathogens. Locher and his coworkers pursue three approaches:
- Determination of the three-dimensional structures of transporters by X-ray crystallography to visualize their ground and intermediate states.
- Investigation of in vitro transport kinetics after reconstitution in artificial lipid bilayers.
- Study of the dynamics of mechanistically relevant conformational changes using biophysical techniques such as fluorescence or electron paramagnetic resonance (EPR) spectroscopy.
Combined, these approaches provide detailed insight into the structure and mechanism of bacterial and eukaryotic ABC transporters, a prerequisite for the development of novel therapeutics.
Recently, Locher has started investigating other classes of transport proteins contributing to drug resistance of pathogenic bacteria and facilitating drug removal from kidney and liver in humans: the multidrug and toxin extrusion (MATE) transporters are potential targets for future drug developments.
locher @ mol.biol.ethz.ch
Function in NCCR
- Principal Investigator (PI)
- Management Comm. Member
Multidrug transporter ABCG2
Associate Professor of Molecular Membrane Biology, Institute of Molecular Biology and Biophysics, Swiss Federal Institute of Technology, Zurich
- Ph.D. in Biochemistry at the University of Basel
- M.Sc. in Biochemistry at the Swiss Federal Institute of Technology, Zurich
- Editor, FEBS Letters
- FEBS Letters Young Investigator Award (2008)