Read about some of the latest publications to come from the Department.
A complex iron-calcium cofactor catalyzing phosphotransfer chemistry. Yong, SC, Roversi, P, Lillington, J, Rodriguez, F, Krehenbrink, M, Zeldin, OB, Garman, EF, Lea, SM and Berks, BC.
The Berks lab, collaborating with the Lea lab in the Dunn School of Pathology, show that a member of the alkaline phosphatase PhoX family binds 2 iron and 3 calcium atoms in a catalytic cofactor that has several distinctive characteristics. This is in contrast to the well characterised alkaline phosphatase PhoA which requires zinc and magnesium. PhoX is as widely distributed as the PhoA family amongst ocean microbes and therefore plays a critical role in the global phosphorus cycle. The presence of iron in the PhoX active site suggests a direct biochemical linkage between the iron and phosphate cycles, which could lead to these elements becoming co-limiting. The relative availability of zinc or iron in low phosphorus environments might therefore drive selection between PhoA and PhoX or between the organisms capable of producing these enzymes. See http://www.bioch.ox.ac.uk/aspsite/index.asp?pageid=1176
Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies. Wright KE, Hjerrild, KA, Bartlett, J, Douglas, AD, Jin, J, Brown, RE, Illingworth, JJ, Ashfield, R, Clemmensen, SB, de Jongh, WA, Draper, SJ and Higgins, MK. Nature (2014) 17 August doi:10.1038/nature13715
Work from Matt Higgins' lab in collaboration with Simon Draper at the Jenner Institute describes the structure of Plasmodium falciparum RH5, the only malarial protein so far shown to be essential in the invasion process, and its interaction with host protein, basigin. By targeting one of the best vaccine candidates for malaria, the work opens the door for the development of a new generation of vaccines against this deadly disease. See http://www.bioch.ox.ac.uk/aspsite/index.asp?pageid=1161
Love-Hate ligands for high resolution analysis of strain in ultra-stable protein/small molecule interaction. Fairhead M, Shen D, Chan LK, Lowe ED, Donohoe TJ, Howarth M. Bioorg Med Chem. 2014 Jul 24. doi: 10.1016/j.bmc.2014.07.029. [Epub ahead of print]
SpyAvidin Hubs Enable Precise and Ultrastable Orthogonal Nanoassembly.?Fairhead M, Veggiani G, Lever M, Yan J, Mesner D, Robinson CV, Dushek O, van der Merwe PA, Howarth M. J Am Chem Soc. 2014 Aug 21. doi: 10.1021/ja505584f
These two papers from Mark Howarth, Michael Fairhead and colleagues describe how they have exploited one of the most widely used tools in biomedical research. The papers outline work on the streptavidin/biotin system whose versatility stems from the exceptionally tight binding of biotin to streptavidin. In the BMC paper, the group describes a new approach to explore the exceptional strength of the streptavidin/biotin interaction at atomic resolution and what happens when a force is applied to it. In the JACS paper, the group engineers robust orthogonal interaction into the streptavidin/biotin hub by combining it with their SpyTag/Catcher technology, increasing the potential for nano-assembly applications. See http://www.bioch.ox.ac.uk/aspsite/index.asp?pageid=1168
Control of cell growth, division and death: information processing in living cells. Tyson, JJ and Novák, B. Interface Focus (2014) 4(3): 20130070
The living cell receives information via surface receptor molecules and internal surveillance mechanisms. Typical responses to this information include growth and division, sexual reproduction, movement, differentiation and cell death. In this review article, the authors describe the development of ideas over the last 50 years that have led to to our current understanding of cellular information processing, particularly related to cell growth, division and death.
Bistability, Oscillations, and Traveling Waves in Frog Egg Extracts. Tyson, JJ and Novák, B. Bull Math Biol. 2014 Sept 4
Mathematical modeling is a powerful tool for unraveling the complexities of the molecular regulatory networks underlying all aspects of cell physiology. To support this claim, the authors review their experiences modeling the cyclin-dependent kinase (CDK) network that controls events of the eukaryotic cell cycle. The model was derived from classic experiments on the biochemistry and molecular genetics of CDKs and their partner proteins. This case study illustrates the novel insights that mathematical modeling, analysis, and simulation can provide cell physiologists, and it points the way to a new “dynamical perspective” on molecular cell biology.
A Multiscale Approach to Modelling Drug Metabolism by Membrane-Bound Cytochrome P450 Enzymes. Lonsdale R, Rouse SL, Sansom MSP and Mulholland AJ (2014). PLoS Comput Biol 10(7): e1003714. doi:10.1371/journal.pcbi.1003714
A significant amount of information about how enzymes and other proteins function has been obtained from computer simulations. Often, the size of the system that is required to provide a sufficiently realistic model places limitations on both the timescale of the simulation, and the level of detail that can be studied. Computational approaches that use more than one type of method (‘multiscale methods’) allow the size of system, and timescale of study, to be increased. Membrane-bound proteins are an example of where multiscale simulations can be used. In this paper the group uses membrane-bound P450, important in drug-metabolism, together with the anticoagulant drug R-warfarin, and presents a simulation piepline that leads through the construction and refinement of a realistic protein:membrane system by molecular dynamics simulations to reaction modelling. The work reveals that a membrane-bound model is required to fully capture the gating mechanisms and substrate ingress/egress channels. The simulation protocol described here is transferrable to other membrane-bound proteins.
A conformational landscape for alginate secretion across the outer membrane of Pseudomonas aeruginosa. Tan J, Rouse SL, Li D, Pye VE, Vogeley L, Brinth AR, El Arnaout T, Whitney JC, Howell PL, Sansom, MSP and Caffrey M. Acta Crys (2014) D70, 2054-2068
The authors report structural details of the export of the exopolysaccharide aliginate, an important component of biofilms produced by Pseudomonas aeruginosa, a major pathogen that affects immune-compromised patients such as those with cystic fibrosis or with burns. The paper presents the X-ray structures of several crystal forms of AlgE, the outer membrane porin through which alginate exits the cell. Together with docking and multiscale molecular-dynamics simulations, the data support a proposed mechanism for aliginate transport.
A molecular mechanism of mitotic centrosome assembly in Drosophila. Conduit PT, Richens JH, Wainman A, Holder J, Vicente CC, Pratt MB, Dix CI, Novak ZA, Dobbie IM, Schermelleh L and Raff JW. eLife 2014;10.7554/eLife.03399
Centrosomes comprise a pair of centrioles surrounded by pericentriolar material (PCM). The PCM expands dramatically as cells enter mitosis, but it is unclear how this occurs. In this paper the authors show that the centriole protein Asl initiates the recruitment of DSpd-2 and Cnn to mother centrioles; both proteins then assemble into co-dependent scaffold-like structures that spread outwards from the mother centriole and recruit most, if not all, other PCM components. In the absence of either DSpd-2 or Cnn mitotic PCM assembly is diminished; in the absence of both proteins it appears to be abolished. DSpd-2 helps incorporate Cnn into the PCM and Cnn then helps maintain DSpd-2 within the PCM, creating a positive feedback loop that promotes robust PCM expansion around the mother centriole during mitosis. These observations suggest a surprisingly simple mechanism of mitotic PCM assembly in flies.
Strain-specific antiviral activity of iminosugars against human influenza A virus. Hussain S, Miller JL, Harvey DJ, Gu Y, Rosenthal PB, Zitzmann N and McCauley JW. J. Antimicrob. Chemother. (2014) doi: 10.1093/jac/dku349
Iminosugar compounds that inhibit host α-glucosidases have been reported to show antiviral activity against multiple viruses. This paper reports the effect and mechanism of two iminosugar α-glucosidase inhibitors on human influenza A viruses. Both compounds showed antiviral activity in cell culture against three human influenza A viruses in a strain-specific manner. Consistent with its action as an α-glucosidase inhibitor, one of the compounds (NN-DNJ) resulted in an altered glycan processing of influenza haemagglutinin (HA) and neuraminidase (NA). NN-DNJ treatment was found to reduce the cell surface expression of the H3 subtype HA. The level of sialidase activity of NA was reduced in infected cells, but the addition of exogenous sialidase to the cells did not complement the NN-DNJ-mediated inhibition of virus replication. The authors conclude that NN-DNJ inhibits influenza A virus replication in a strain-specific manner that is dependent on the HA.