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• Journal article
  Douse CH, Green JL, Salgado PS, Simpson PJ, Thomas JC, Langsley G, Holder AA, Tate EW, Cota Eet al., 2012,

  Regulation of the Plasmodium motor complex: phosphorylation of myosin A tail-interacting protein (MTIP) loosens its grip on MyoA.

  , Journal of Biological Chemistry, Vol: 287, Pages: 36968-36977, ISSN: 1083-351X

  Background: Recent phosphoproteome data reveal the extent of post-translational phosphorylation in selected apicomplexanparasites.Results: Binding site mutants that mimic the effect of MTIP phosphorylation in vivo severely decrease MyoA binding.Conclusion: Phosphorylation of selected binding site residues modulates the activity of the actomyosin motor.Significance: Study of Apicomplexa phosphosites can inform on the regulation of functions involved in pathogenesis.

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• Journal article
  Yu Z, Brannigan JA, Moss DK, Brzozowski AM, Wilkinson AJ, Holder AA, Tate EW, Leatherbarrow RJet al., 2012,

  Design and Synthesis of Inhibitors of Plasmodium falciparum N-Myristoyltransferase, A Promising Target for Antimalarial Drug Discovery

  , Journal of Medicinal Chemistry, Vol: 55, Pages: 8879-8890, ISSN: 0022-2623

  Design of inhibitors for N-myristoyltransferase (NMT), an enzyme responsible for protein trafficking in Plasmodium falciparum, the most lethal species of parasites that cause malaria, is described. Chemistry-driven optimization of compound 1 from a focused NMT inhibitor library led to the identification of two early lead compounds 4 and 25, which showed good enzyme and cellular potency and excellent selectivity over human NMT. These molecules provide a valuable starting point for further development.

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• Journal article
  Thinon E, Mann D, Tate EW, 2012,

  Targeting N-myristoyl transferase-1 in cancer using peptide microarrays

  , Journal of Peptide Science, Vol: 18, Pages: S75-S75, ISSN: 1099-1387
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• Journal article
  Price HP, Hodgkinson MR, Wright MH, Tate EW, Smith BA, Carrington M, Stark M, Smith DFet al., 2012,

  A role for the vesicle-associated tubulin binding protein ARL6 (BBS3) in flagellum extension in Trypanosoma brucei

  , Biochimica et Biophysica Acta-Molecular Cell Research, Vol: 1823, Pages: 1178-1191, ISSN: 0167-4889

  The small GTPase Arl6 is implicated in the ciliopathic human genetic disorder Bardet–Biedl syndrome, actingat primary cilia in recruitment of the octomeric BBSome complex, which is required for specific traffickingevents to and from the cilium in eukaryotes. Here we describe functional characterisation of Arl6 in the flagellatedmodel eukaryote Trypanosoma brucei, which requires motility for viability. Unlike human Arl6 whichhas a ciliary localisation, TbARL6 is associated with electron-dense vesicles throughout the cell body followingco-translational modification by N-myristoylation. Similar to the related protein ARL-3A in T. brucei, modulationof expression of ARL6 by RNA interference does not prevent motility but causes a significant reductionin flagellum length. Tubulin is identified as an ARL6 interacting partner, suggesting that ARL6 may act as ananchor between vesicles and cytoplasmic microtubules. We provide evidence that the interaction betweenARL6 and the BBSome is conserved in unicellular eukaryotes. Overexpression of BBS1 leads to translocationof endogenous ARL6 to the site of exogenous BBS1 at the flagellar pocket. Furthermore, a combination ofBBS1 overexpression and ARL6 RNAi has a synergistic inhibitory effect on cell growth. Our findings indicatethat ARL6 in trypanosomes contributes to flagellum biogenesis, most likely through an interaction with theBBSome

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• Conference paper
  Konitsiotis A, Chang S, Masumoto N, Tate EW, Magee AIet al., 2012,

  Hhat a Potential New Target in Treatment of Pancreatic Cancer

  , 22nd Biennial Congress of the European-Association-for-Cancer-Research, Publisher: ELSEVIER SCI LTD, Pages: S149-S149, ISSN: 0959-8049
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• Journal article
  Bell AS, Mills JE, Williams GP, Brannigan JA, Wilkinson AJ, Parkinson T, Leatherbarrow RJ, Tate EW, Holder AA, Smith DFet al., 2012,

  Selective Inhibitors of Protozoan Protein N-myristoyltransferases as Starting Points for Tropical Disease Medicinal Chemistry Programs

  , PLOS Neglected Tropical Diseases, Vol: 6, ISSN: 1935-2735

  Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal andtrypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose toscreen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs.Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) andfor broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. Analysis of the screening results hasshown that structure-activity relationships (SAR) for Leishmania NMT are divergent from all other NMTs tested, a finding notpredicted by sequence similarity calculations, resulting in the identification of four novel series of Leishmania-selective NMTinhibitors. We found a strong overlap between the SARs for Plasmodium NMT and both human NMTs, suggesting thatachieving an appropriate selectivity profile will be more challenging. However, we did discover two novel series withselectivity for Plasmodium NMT over the other NMT orthologues in this study, and an additional two structurally distinctseries with selectivity over Leishmania NMT. We believe that release of results from this study into the public domain willaccelerate the discovery of NMT inhibitors to treat malaria and leishmaniasis. Our screening initiative is another example ofhow a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/nongovernmentalorganisations such as Medical Research Council and Wellcome Trust can stimulate research for neglecteddiseases

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• Journal article
  Goncalves V, Brannigan JA, Whalley D, Ansell KH, Saxty B, Holder AA, Wilkinson AJ, Tate EW, Leatherbarrow RJet al., 2012,

  Discovery of Plasmodium vivax N-Myristoyltransferase Inhibitors: Screening, Synthesis, and Structural Characterization of their Binding Mode

  , Journal of Medicinal Chemistry, Vol: 55, Pages: 3578-3582, ISSN: 0022-2623

  N-Myristoyltransferase (NMT) is a prospective drug target against parasitic protozoa. Herein we report the successful discovery of a series of Plasmodium vivax NMT inhibitors by high-throughput screening. A high-resolution crystal structure of the hit compound in complex with NMT was obtained, allowing understanding of its novel binding mode. A set of analogues was designed and tested to define the chemical groups relevant for activity and selectivity.

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• Conference paper
  Bradshaw RT, Aronica PGA, Tate EW, Leatherbarrow RJ, Gould IRet al., 2012,

  Developing mutational locally enhanced sampling (MULES) for predicting relative binding free energies at protein-protein interfaces

  , 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS), Publisher: AMER CHEMICAL SOC, ISSN: 0065-7727
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• Journal article
  Goncalves V, Brannigan JA, Thinon E, Olaleye TO, Serwa R, Lanzarone S, Wilkinson AJ, Tate EW, Leatherbarrow RJet al., 2012,

  A fluorescence-based assay for N-myristoyltransferase activity

  , Analytical Biochemistry, Vol: 421, Pages: 342-344, ISSN: 1096-0309

  N-myristoylation is the irreversible attachment of a C14 fatty acid, myristic acid, to the N-terminal glycine of a protein via formation of an amide bond. This modification is catalyzed by myristoyl–coenzyme A (CoA):protein N-myristoyltransferase (NMT), an enzyme ubiquitous in eukaryotes that is up-regulated in several cancers. Here we report a sensitive fluorescence-based assay to study the enzymatic activity of human NMT1 and NMT2 based on detection of CoA by 7-diethylamino-3-(4-maleimido-phenyl)-4-methylcoumarin. We also describe expression and characterization of NMT1 and NMT2 and assay validation with small molecule inhibitors. This assay should be broadly applicable to NMTs from a range of organisms.

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• Journal article
  Broncel M, Serwa RA, Tate EW, 2012,

  A New Chemical Handle for Protein AMPylation at the Host-Pathogen Interface

  , Chembiochem, Vol: 13, Pages: 183-185, ISSN: 1439-7633

  agging protein AMPylation: A new chemical reporter for AMPylation, recently identified as a key post-translational modification during bacterial infection, is a robust tool for detecting and identifying AMPylated proteins in vitro.

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