Professor Bert van den Berg
Prof of Membrane Protein Structural Biology
- Email: email@example.com
- Telephone: +44 (0) 191 208 8122
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
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
2005: Elected a PEW scholar in the Biomedical Sciences.
2013: Royal Society Wolfson Research Merit Award
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)
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
practical membrane protein purification (BGM2061)
- Pathania M, Acosta-Gutierrez S, Bhamidimarri SP, Basle A, Ceccarelli M, Winterhalter M, van den Berg B. Unusual constriction zones in the major porins OmpU and OmpT from Vibrio cholerae. Structure 2018, 26(5), 708-721.
- Aunkham A, Zahn M, Kesireddy A, Pothula KR, Schulte A, Basle A, Kleinekathofer U, Suginta W, van den Berg B. Structural basis for chitin acquisition by marine Vibrio species. Nature Communications 2018, 9(1), 220.
- Bolam DN, van den Berg B. TonB-dependent transport by the gut microbiota: novel aspects of an old problem. Current Opinion in Structural Biology 2018, 51, 35-43.
- Abellón-Ruiz J, Kaptan SS, Baslé A, Claudi B, Bumann D, Kleinekathöfer U, van den Berg B. Structural basis for maintenance of bacterial outer membrane lipid asymmetry. Nature Microbiology 2017, epub ahead of print.
- Arunmanee W, Pathania M, Solovyova AS, Le Brun AP, Ridley H, Baslé A, van den Berg B, Lakey JH. Gram-negative trimeric porins have specific LPS binding sites that are essential for porin biogenesis. Proceedings of the National Academy of Sciences of the USA 2016, 113(34), E5034-E5043.
- Bhamidimarri SP, Prajapati JD, van den Berg B, Winterhalter M, Kleinekathöfer U. Role of Electroosmosis in the Permeation of Neutral Molecules: CymA and Cyclodextrin as an Example. Biophysical Journal 2016, 110(3), 600-611.
- van den Berg B, Chembath A, Jefferies D, Basle A, Khalid S, Rutherford JC. Structural basis for Mep2 ammonium transceptor activation by phosphorylation. Nature Communications 2016, 7, 11337.
- Zahn M, Bhamidimarri SP, Basle A, Winterhalter M, van den Berg B. Structural Insights into Outer Membrane Permeability of Acinetobacter baumannii. Structure 2016, 24(2), 221-231.
- van den Berg B, Bhamidimarri SP, Winterhalter M. Crystal structure of a COG4313 outer membrane channel. Scientific Reports 2015, 5, 11927.
- van den Berg B, Prathyusha BS, Dahyabhai PJ, Kleinekathöfer U, Winterhalter M. Outer-membrane translocation of bulky small molecules by passive diffusion. Proceedings of the National Academy of Sciences of the United States of America 2015, 112(23), E2991-E2999.
- Cheneke BR, van den Berg B, Movileanu L. Quasithermodynamic contributions to the fluctuations of a protein nanopore. ACS Chemical Biology 2015, 10(3), 784–794.
- Zahn M, D'Agostino T, Eren E, Baslé A, Ceccarelli M, van den Berg B. Small-Molecule Transport by CarO, an Abundant Eight-Stranded β-Barrel Outer Membrane Protein from Acinetobacter baumannii. Journal of Molecular Biology 2015, 427(14), 2329-2339.
- Modi N, Ganguly S, Bárcena-Uribarri I, Benz R, van den Berg B, Kleinekathöfer U. Structure, Dynamics, and Substrate Specificity of the OprO Porin from Pseudomonas aeruginosa. Biophysical Journal 2015, 109(7), 1429-1438.
- van den Berg B. Lateral gates: β-barrels get in on the act. Nature Structural and Molecular Biology 2013, 20(11), 1237-1239.
- Malaby AW, van den Berg B, Lambright DG. Structural basis for membrane recruitment and allosteric activation of cytohesin family Arf GTPase exchange factors. Proc Natl Acad Sci USA 2013, 110(35), 14213-14218.
- Eren E, Parkin J, Adelanwa A, Cheneke B, Movileanu L, Khalid S, van den Berg B. Towards understanding of outer membrane uptake of small molecules by Pseudomonas aeruginosa. Journal of Biological Chemistry 2013, 288(17), 2042-20453.
- Cheneke BR, Indic M, van den Berg B, Movileanu L. An outer membrane protein undergoes enthalpy- and entropy-driven transitions. Biochemistry 2012, 51(26), 5348-5358.
- Liu J, Wolfe AJ, Eren E, Vijayaraghavan J, Indic M, van den Berg B, Movileanu L. Cation selectivity is a conserved feature in the OccD subfamily of Pseudomonas aeruginosa. Biochim Biophys Acta: Biomembranes 2012, 1818(11), 2908-2916.
- Liu J, Eren E, Vijayaraghavan J, Cheneke BR, Indic M, van den Berg B, Movileanu L. OccK channels from Pseudomonas aeruginosa exhibit diverse single-channel electrical signatures but conserved anion selectivity. Biochemistry 2012, 51(11), 2319-2330.
- Eren E, van den Berg B. Structural basis for activation of an integral membrane protease by lipopolysaccharide. Journal of Biological Chemistry 2012, 287(28), 23971-23976.
- van den Berg B. Structural basis for outer membrane sugar uptake in pseudomonads. Journal of Biological Chemistry 2012, 287(49), 41044-41052.
- Eren E, Vijayaraghavan J, Liu J, Cheneke BR, Touw DS, Lepore BW, Indic M, Movileanu L, van den Berg B. Substrate specificity within a family of outer membrane carboxylate channels. PLoS Biology 2012, 10(1), e1001242.
- Cheneke BR, van den Berg B, Movileanu L. Analysis of Gating Transitions among the Three Major Open States of the OpdK Channel. Biochemistry 2011, 50(22), 4987-4997.
- Kulathila R, Kulathila R, Indic M, van den Berg B. Crystal structure of Escherichia coli CusC, the outer membrane component of a heavy metal efflux pump. PLoS One 2011, 6(1), e15610.
- Lepore BW, Indic M, Pham H, Hearn EM, Patel DR, van den Berg B. Ligand-gated diffusion across the bacterial outer membrane. Proceedings of the National Academy of Sciences 2011, 108(25), 10121-10126.
- Eren E, Murphy M, Goguen J, van den Berg B. An active site water network in the plasminogen activator pla from Yersinia pestis. Structure 2010, 18(7), 809-818.
- van den Berg B. Crystal structure of a full-length autotransporter. Journal of Molecular Biology 2010, 396(3), 627-633.
- van den Berg B. Going forward laterally: transmembrane passage of hydrophobic molecules through protein channel walls. Chembiochem 2010, 11(10), 1339-1343.
- Touw DS, Patel DR, van den Berg B. The crystal structure of OprG from Pseudomonas aeruginosa, a potential channel for transport of hydrophobic molecules across the outer membrane. PLoS One 2010, 5(11), e15016.
- Hearn EM, Patel DR, Lepore BW, Indic M, van den Berg B. Transmembrane passage of hydrophobic compounds through a protein channel wall. Nature 2009, 458(7236), 367-370.
- Biswas S, Mohammad MM, Movileanu L, van den Berg B. Crystal structure of the outer membrane protein OpdK from Pseudomonas aeruginosa. Structure 2008, 16(7), 1027-35.
- Hearn EM, Patel DR, van den Berg B. Outer-membrane transport of aromatic hydrocarbons as a first step in biodegradation. Proceedings of the National Academy of Sciences 2008, 105(25), 8601-8606.
- Biswas S, Mohammad MM, Patel DR, Movileanu L, van den Berg B. Structural insight into OprD substrate specificity. Nat Struct Mol Biol 2007, 14(11), 1108-9.
- Subbarao GV, van den Berg B. Crystal structure of the monomeric porin OmpG. J Mol Biol 2006, 360(4), 750-9.
- Hong H, Patel DR, Tamm LK, van den Berg B. The outer membrane protein OmpW forms an eight-stranded beta-barrel with a hydrophobic channel. J Biol Chem 2006, 281(11), 7568-77.
- Osborne AR, Rapoport TA, van den Berg B. Protein translocation by the Sec61/SecY channel. Annu Rev Cell Dev Biol 2005, 529-50.
- van den Berg B. The FadL family: unusual transporters for unusual substrates. Curr Opin Struct Biol 2005, 15(4), 401-7.
- Ye J, van den Berg B. Crystal structure of the bacterial nucleoside transporter Tsx. EMBO Journal 2004, 23(16), 3187-3195.
- van den Berg B, Black PN, Clemons WM Jr, Rapoport TA. Crystal structure of the long-chain fatty acid transporter FadL. Science 2004, 304(5676), 1506-1509.
- Van den Berg B, Clemons WM Jr, Collinson I, Modis Y, Hartmann E, Harrison SC, Rapoport TA. X-ray structure of a protein-conducting channel. Nature 2004, 427(6969), 36-44.
- Suginta W, Sritho N, Ranok A, Bulmer DM, Kitaoku Y, van den Berg B, Fukamizo T. Structure and function of a novel periplasmic chitooligosaccharide-binding protein from marine Vibrio bacteria. Journal of Biological Chemistry 2018, 293(14), 5150-5159.