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  • Journal article
    Berry AFH, Heal WP, Tarafder AK, Tolmachova T, Baron RA, Seabra MC, Tate EWet al., 2010,

    Rapid Multilabel Detection of Geranylgeranylated Proteins by Using Bioorthogonal Ligation Chemistry

    , CHEMBIOCHEM, Vol: 11, Pages: 771-773, ISSN: 1439-4227
  • Journal article
    Brannigan JA, Smith BA, Yu Z, Brzozowski AM, Hodgkinson MR, Maroof A, Price HP, Meier F, Leatherbarrow RJ, Tate EW, Smith DF, Wilkinson AJet al., 2010,

    N-Myristoyltransferase from Leishmania donovani: Structural and Functional Characterisation of a Potential Drug Target for Visceral Leishmaniasis

    , Journal of Molecular Biology, Vol: 396, Pages: 985-999, ISSN: 1089-8638

    N-Myristoyltransferase (NMT) catalyses the attachment of the 14-carbon saturated fatty acid, myristate, to the amino-terminal glycine residue of a subset of eukaryotic proteins that function in multiple cellular processes, including vesicular protein trafficking and signal transduction. In these pathways, N-myristoylation facilitates association of substrate proteins with membranes or the hydrophobic domains of other partner peptides. NMT function is essential for viability in all cell types tested to date, demonstrating that this enzyme has potential as a target for drug development. Here, we provide genetic evidence that NMT is likely to be essential for viability in insect stages of the pathogenic protozoan parasite, Leishmania donovani, causative agent of the tropical infectious disease, visceral leishmaniasis. The open reading frame of L. donovaniNMT has been amplified and used to overproduce active recombinant enzyme in Escherichia coli, as demonstrated by gel mobility shift assays of ligand binding and peptide-myristoylation activity in scintillation proximity assays. The purified protein has been crystallized in complex with the non-hydrolysable substrate analogue S-(2-oxo)pentadecyl-CoA, and its structure was solved by molecular replacement at 1.4 Å resolution. The structure has as its defining feature a 14-stranded twisted β-sheet on which helices are packed so as to form an extended and curved substrate-binding groove running across two protein lobes. The fatty acyl-CoA is largely buried in the N-terminal lobe, its binding leading to the loosening of a flap, which in unliganded NMT structures, occludes the protein substrate binding site in the carboxy-terminal lobe. These studies validate L. donovani NMT as a potential target for development of new therapeutic agents against visceral leishmaniasis.

  • Journal article
    Dang THT, de la Riva L, Fagan RP, Storck EM, Heal WP, Janoir C, Fairweather NF, Tate EWet al., 2010,

    Chemical Probes of Surface Layer Biogenesis in Clostridium difficile

    , ACS CHEMICAL BIOLOGY, Vol: 5, Pages: 279-285, ISSN: 1554-8929
  • Journal article
    So S, Peeva LG, Tate EW, Leatherbarrow RJ, Livingston AGet al., 2010,

    Membrane enhanced peptide synthesis

    , CHEMICAL COMMUNICATIONS, Vol: 46, Pages: 2808-2810, ISSN: 1359-7345
  • Journal article
    Thomas JC, Green JL, Howson RI, Simpson P, Moss DK, Martin SR, Holder AA, Cota E, Tate EWet al., 2010,

    Interaction and dynamics of the Plasmodium falciparum MTIP-MyoA complex, a key component of the invasion motor in the malaria parasite

    , MOLECULAR BIOSYSTEMS, Vol: 6, Pages: 494-498, ISSN: 1742-206X
  • Journal article
    Heal WP, Tate EW, 2010,

    Getting a chemical handle on protein post-translational modification

    , ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 8, Pages: 731-738, ISSN: 1477-0520
  • Journal article
    So S, Peeva LG, Tate EW, Leatherbarrow RJ, Livingston AGet al., 2010,

    Organic Solvent Nanofiltration: A New Paradigm in Peptide Synthesis

    , Org Process Res Dev, Vol: 14, Pages: 1313-1325
  • Journal article
    Wright MH, Heal WP, Mann DJ, Tate EWet al., 2010,

    Protein myristoylation in health and disease.

    , J Chem Biol, Vol: 3, Pages: 19-35, ISSN: 1864-6166

    N-myristoylation is the attachment of a 14-carbon fatty acid, myristate, onto the N-terminal glycine residue of target proteins, catalysed by N-myristoyltransferase (NMT), a ubiquitous and essential enzyme in eukaryotes. Many of the target proteins of NMT are crucial components of signalling pathways, and myristoylation typically promotes membrane binding that is essential for proper protein localisation or biological function. NMT is a validated therapeutic target in opportunistic infections of humans by fungi or parasitic protozoa. Additionally, NMT is implicated in carcinogenesis, particularly colon cancer, where there is evidence for its upregulation in the early stages of tumour formation. However, the study of myristoylation in all organisms has until recently been hindered by a lack of techniques for detection and identification of myristoylated proteins. Here we introduce the chemistry and biology of N-myristoylation and NMT, and discuss new developments in chemical proteomic technologies that are meeting the challenge of studying this important co-translational modification in living systems.

  • Journal article
    Thongyoo P, Bonomelli C, Leatherbarrow RJ, Tate EWet al., 2009,

    Potent Inhibitors of beta-Tryptase and Human Leukocyte Elastase Based on the MCoTI-II Scaffold

    , JOURNAL OF MEDICINAL CHEMISTRY, Vol: 52, Pages: 6197-6200, ISSN: 0022-2623
  • Journal article
    Heal WP, Wickramasinghe SR, Tate EW, 2008,

    Activity based chemical proteomics: profiling proteases as drug targets.

    , Curr Drug Discov Technol, Vol: 5, Pages: 200-212, ISSN: 1570-1638

    The pivotal role of proteases in many diseases has generated considerable interest in their basic biology, and in the potential to target them for chemotherapy. Although fundamental to the initiation and progression of diseases such as cancer, diabetes, arthritis and malaria, in many cases their precise role remains unknown. Activity-based chemical proteomics-an emerging field involving a combination of organic synthesis, biochemistry, cell biology, biophysics and bioinformatics-allows the detection, visualisation and activity quantification of whole families or selected sub-sets of proteases based upon their substrate specificity. This approach can be applied for drug target/lead identification and validation, the fundamentals of drug discovery. The activity-based probes discussed in this review contain three key features; a 'warhead' (binds irreversibly but selectively to the active site), a 'tag' (allowing enzyme 'handling', with a combination of fluorescent, affinity and/or radio labels), and a linker region between warhead and tag. From the design and synthesis of the linker arise some of the latest developments discussed here; not only can the physical properties (e.g., solubility, localisation) of the probe be tuned, but the inclusion of a cleavable moiety allows selective removal of tagged enzyme from affinity beads etc. The design and synthesis of recently reported probes is discussed, including modular assembly of highly versatile probes via solid phase synthesis. Recent applications of activity-based protein profiling to specific proteases (serine, threonine, cysteine and metalloproteases) are reviewed as are demonstrations of their use in the study of disease function in cancer and malaria.

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