Centre for Bacterial Cell Biology

Staff Profile

Professor Bert van den Berg

Prof of Membrane Protein Structural Biology

Background

Education and Research positions

 

1995-1996: Postdoctoral research fellow, Inorganic chemistry, University of Oxford, Oxford, UK

1997: Postdoctoral research fellow, Physical Chemistry, University of Granada, Granada, Spain

1998-1999: Postdoctoral research fellow, Inorganic Chemistry, University of Oxford, Oxford, UK

2000-2004: Postdoctoral research fellow, Cell Biology, Howard Hughes Medical Institute and Harvard Medical School, Boston, MA

 

Academic positions

2004-2009: Assistant Professor, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA

2009-2012: Associate Professor, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA (tenure awarded in 2012)

2013- : Professor in Membrane Protein Structural Biology, Institute for Cellular and Molecular Biosciences, Newcastle University, UK

 

Awards

2005: Elected a PEW scholar in the Biomedical Sciences.

2013: Royal Society Wolfson Research Merit Award

 

Current Grants

NIH 1R01GM104495-01 Understanding aromatic hydrocarbon uptake as the first step in biodegradation (2013-2016; PI)

Innovative Medicines Initiative (IMI) Translocation: Molecular basis of the bacterial cell wall permeability (part of the EU program New Drugs for Bad Bugs)  (2013-2017; consortium partner)

 

Research

I joined the Institute of Cellular and Molecular Biosciences at Newcastle University in January 2013. Prior to coming to the UK, I was a faculty member within the Program in Molecular Medicine at UMass Medical School in Worcester, Massachusetts. The main focus of my research is to understand how small molecules are transported across the outer membrane (OM) of Gram-negative bacteria. For this, we determine the three-dimensional structures of bacterial integral OM proteins by X-ray crystallography. Those structures are then used, in combination with functional data obtained from biochemical experiments, to propose models that can be tested experimentally. In addition to OM uptake channels, we have solved structures of an OM protease (Pla), a full-length autotransporter (EstA) and the OM component of a metal efflux pump (CusC).

At the moment, our research on OM proteins is focused around two major themes:

1. Transport of hydrophobic molecules.

The uptake of hydrophobic molecules such as long-chain fatty acids (LCFA) and aromatic hydrocarbons across the OM requires special uptake proteins due to the presence of LPS on the outside of the cell. The best-known examples are FadL channels, which are found in most Gram-negative bacteria. Our future research on FadL-mediated transport will focus on the uptake of environmental pollutants ("xenobiotics") during biodegradation. Most pollutants (e.g. aromatic hydrocarbons) are hydrophobic and require dedicated transport channels for uptake and subsequent metabolization in the cytoplasm. Our model system is Pseudomonas putida F1 (PpF1), a versatile, well-characterized biodegrader capable of metabolizing mono-aromatic hydrocarbons (MAH) such as benzene and toluene. PpF1 has three FadL orthologs, two of which have been crystallized by my lab (TodX and CymD). Interestingly, the channels that transport toluene (TodX, CymD) do not transport LCFA, and vice versa. Explaining this difference in substrate specificity is one of the goals of our research. In addition, we would like to answer the following questions:

1. What is the transport mechanism for MAH? Preliminary data suggest that the mechanism might be different from lateral diffusion. 2. How important are FadL channels under conditions that resemble the natural environment? 3. Which cellular adaptations are required for growth of PpF1 on MAH? Given the fact that MAH make membranes leaky, we are especially interested in the identification of changes related to (phospho)lipid metabolism.

Because FadL orthologs are found in many biodegrading bacteria, our research is relevant for the bioremediation of xenobiotics within the environment.

 

2. Understanding OM antibiotics uptake.

The increasing emergence of pathogenic (Gram-negative) bacteria that are resistant towards antibiotics represents a big future threat for public health, a situation that has recently been likened to a "ticking time bomb" and a possible "apocalypse" by the chief medical officer of England (http://www.bbc.co.uk/news/health-21702647). New antibiotics are therefore urgently needed. Despite this pressing need, very few new antibiotics have reached the market in the last decade, owing to the huge problems and risks in drug design. It is clear that the successful design of effective antibacterials requires detailed insights in the basic biology of influx and efflux. In Gram-negative bacteria, the OM is the first (and frequently only) barrier encountered by antibiotics; consequently, drugs need to pass through OM channels in order to enter the cell. Indeed, changes in the levels of functional OM channels have been linked to resistance in many cases. We study the transport of antibiotics through OM diffusion channels to aid the design of drugs with efficient permeation properties. We are focusing on the channels of Pseudomonas aeruginosa (Pa) and Acinetobacter baumannii (Ab), two pathogens that are notorious for their resistance towards antibiotics. This is due to the extremely low permeability of the OM, which in turn is caused by the restrictive nature of the OM transport proteins. Pa contains ~30 OM uptake channels, whereas Ab may possess ~10-15.

Our future work on this project will take place within an exciting, recently established EU consortium consisting of a number of academic labs, small biotech firms and big pharma (http://www.imi.europa.eu/content/translocation). A major focus of my group will lie on characterization (co-crystal structures, binding/transport profiles) of the interactions of antibiotics with channels that are important and/or highly expressed during infection. Those channels will be identified using OM proteomics (Dirk Bumann, Biozentrum Basel). Other close collaborators within the consortium include electrophysiologists (Mathias Winterhalter, Jacobs-University Bremen) and computational biologists (Ulrich Kleinekathoefer, Jacobs-University Bremen and Matteo Ceccarelli, University of Cagliari). The overall goal of the project is to obtain atomistic, quantitative descriptions of antibiotics passage through relevant OM channels. The obtained insights will likely aid the design of novel antibiotics with superior permeation properties.

 

Besides OM proteins, the lab also has an interest in alpha-helical membrane proteins, in particular those involved in ammonium transport in fungi (Mep2) and the mammalian copper transporter Ctr1. To this latter end we are also expressing membrane proteins in the yeast Saccharomyces cerevisiae.

For more information about our research (with pictures!), please visit the website of the Newcastle Structural Biology Laboratory:  http://sbl.ncl.ac.uk/people/bert_research.shtml

Teaching

BGM2061

practical membrane protein purification (BGM2061)

BGM2062

BGM3064

Publications