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• Journal article
  Anderson DP, Benns HJ, Tate EW, Child MAet al., 2020,

  CRISPR-TAPE: protein-centric CRISPR guide design for targeted proteome engineering.

  , Mol Syst Biol, Vol: 16

  Rational molecular engineering of proteins with CRISPR-based approaches is challenged by the gene-centric nature of gRNA design tools. To address this, we have developed CRISPR-TAPE, a protein-centric gRNA design algorithm that allows users to target specific residues, or amino acid types within proteins. gRNA outputs can be customized to support maximal efficacy of homology-directed repair for engineering purposes, removing time-consuming post hoc curation, simplifying gRNA outputs and reducing CPU times.

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• Journal article
  Kounde C, Shchepinova M, Saunders C, Muelbaier M, Rackham M, Harling J, Tate Eet al., 2020,

  A caged E3 ligase ligand for PROTAC-mediated protein degradation with light

  , Chemical Communications, Vol: 56, Pages: 5532-5535, ISSN: 1359-7345

  With the intent of achieving greater spatiotemporal control of PROTAC-induced protein degradation, a light-activated degrader was designed by photocaging an essential E3 ligase binding motif in a BRD4 targeting PROTAC. Proteolysis was triggered only after a short irradiation time, the kinetics of which could be monitored by live-cell video microscopy.

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• Journal article
  Ward JA, Pinto-Fernandez A, Cornelissen L, Bonham S, Diaz-Saez L, Riant O, Huber KVM, Kessler BM, Feron O, Tate EWet al., 2020,

  Re-Evaluating the Mechanism of Action of alpha,beta-Unsaturated Carbonyl DUB Inhibitors b-AP15 and VLX1570: A Paradigmatic Example of Unspecific Protein Cross-linking with Michael Acceptor Motif-Containing Drugs

  , JOURNAL OF MEDICINAL CHEMISTRY, Vol: 63, Pages: 3756-3762, ISSN: 0022-2623
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• Journal article
  Tzakoniati F, Xu H, Garcia N, Kugel C, Payandeh J, Koth CM, Tate Eet al., 2020,

  Development of photocrosslinking probes based on Huwentoxin-IV to map the site of interaction on Nav1.7

  , Cell Chemical Biology, Vol: 27, Pages: 306-313.e4, ISSN: 2451-9456

  Voltage-gated sodium (Nav) channels respond to changes in the membrane potential of excitable cells through the concerted action of four voltage-sensor domains (VSDs). Subtype Nav1.7 plays an important role in the propagation of signals in pain-sensing neurons and is a target for the clinical development of novel analgesics. Certain inhibitory cystine knot (ICK) peptides produced by venomous animals potently modulate Nav1.7, however the molecular mechanisms underlying their selective binding and activity remain elusive. This study reports on the design of a library of photoprobes based on the potent spider toxin Huwentoxin-IV and the determination of the toxin binding interface on VSD2 of Nav1.7 through a photocrosslinking and tandem mass spectrometry approach. Our Huwentoxin-IV probes selectively crosslink to extracellular loop S1-2 and helix S3 of VSD2 in a chimeric channel system. Our results provide a strategy that will enable mapping of sites of interaction of other ICK peptides on Nav channels.

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• Journal article
  Rueda-Zubiaurre A, Yahiya S, Fischer O, Hu X, Saunders C, Sharma S, Straschil U, Shen J, Tate EW, Delves M, Baum J, Barnard A, Fuchter MJet al., 2020,

  Structure-activity relationship studies of a novel class of transmission blocking antimalarials targeting male gametes.

  , Journal of Medicinal Chemistry, Vol: 63, Pages: 2240-2262, ISSN: 0022-2623

  Malaria is still a leading cause of mortality among children in the developing world, and despite the immense progress made in reducing the global burden, further efforts are needed if eradication is to be achieved. In this context, targeting transmission is widely recognized as a necessary intervention towards that goal. After carrying out a screen to discover new transmission-blocking agents, herein we report our medicinal chemistry efforts to study the potential of the most robust hit, DDD01035881, as a male-gamete targeted compound. We reveal key structural features for the activity of this series and identify analogues with greater potency and improved metabolic stability. We believe this study lays the groundwork for further development of this series as a transmission blocking agent.

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• Journal article
  Dian C, Inmaculada P-D, Riviere F, Asensio T, Legrand P, Ritzefeld M, Shen M, Cota E, Meinnel T, Tate E, Giglione Cet al., 2020,

  High-resolution snapshots of human N-myristoyltransferase in action illuminate a mechanism promoting N-terminal Lys and Gly myristoylation

  , Nature Communications, Vol: 11, Pages: 1-15, ISSN: 2041-1723

  The promising drug target N-myristoyltransferase (NMT) catalyses an essential protein modification thought to occur exclusively at N-terminal glycines (Gly). Here, we present high-resolution human NMT1 structures co-crystallised with reactive cognate lipid and peptide substrates, revealing high-resolution snapshots of the entire catalytic mechanism from the initial to final reaction states. Structural comparisons, together with biochemical analysis, provide unforeseen details about how NMT1 reaches a catalytically competent conformation in which the reactive groups are brought into close proximity to enable catalysis. We demonstrate that this mechanism further supports efficient and unprecedented myristoylation of an N-terminal lysine side chain, providing evidence that NMT acts both as N-terminal-lysine and glycine myristoyltransferase.

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• Journal article
  Lucy D, Zhang L, Tate EW, 2020,

  A Natural Product Puts Malaria on a Low-Fat Diet

  , CELL CHEMICAL BIOLOGY, Vol: 27, Pages: 137-139, ISSN: 2451-9448
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• Journal article
  Howard RT, Hemsley P, Petteruti P, Saunders CN, Molina Bermejo JA, Scott JS, Johannes JW, Tate EWet al., 2020,

  Structure-guided design and in-cell target profiling of a cell-active target engagement probe for PARP inhibitors

  , ACS Chemical Biology, Vol: 15, Pages: 325-333, ISSN: 1554-8929

  Inhibition of the poly(ADP-ribose) polymerase (PARP) family of enzymes has become an attractive therapeutic strategy in oncology and beyond; however, chemical tools to profile PARP engagement in live cells are lacking. Herein, we report the design and application of PARPYnD, the first photoaffinity probe (AfBP) for PARP enzymes based on triple PARP1/2/6 inhibitor AZ9482, which induces multipolar spindle (MPS) formation in breast cancer cells. PARPYnD is a robust tool for profiling PARP1/2 and is used to profile clinical PARP inhibitor olaparib, identifying several novel off-target proteins. Surprisingly, while PARPYnD can enrich recombinant PARP6 spiked into cellular lysates and inhibits PARP6 in cell-free assays, it does not label PARP6 in intact cells. These data highlight an intriguing biomolecular disparity between recombinant and endogenous PARP6. PARPYnD provides a new approach to expand our knowledge of the targets of this class of compounds and the mechanisms of action of PARP inhibitors in cancer.

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• Journal article
  Benfield CT, MacKenzie F, Ritzefeld M, Mazzon M, Weston S, Tate E, Teo BH, Smith SE, Kellam P, Holmes EC, Marsh Met al., 2020,

  Bat IFITM3 restriction depends on S-palmitoylation and a polymorphic site within the CD225 domain

  , Life Science Alliance, Vol: 3, ISSN: 2575-1077

  Host interferon-induced transmembrane proteins (IFITMs) are broad-spectrum antiviral restriction factors. Of these, IFITM3 potently inhibits viruses that enter cells through acidic endosomes, many of which are zoonotic and emerging viruses with bats (order Chiroptera) as their natural hosts. We previously demonstrated that microbat IFITM3 is antiviral. Here, we show that bat IFITMs are characterized by strong adaptive evolution and identify a highly variable and functionally important site-codon 70-within the conserved CD225 domain of IFITMs. Mutation of this residue in microbat IFITM3 impairs restriction of representatives of four different virus families that enter cells via endosomes. This mutant shows altered subcellular localization and reduced S-palmitoylation, a phenotype copied by mutation of conserved cysteine residues in microbat IFITM3. Furthermore, we show that microbat IFITM3 is S-palmitoylated on cysteine residues C71, C72, and C105, mutation of each cysteine individually impairs virus restriction, and a triple C71A-C72A-C105A mutant loses all restriction activity, concomitant with subcellular re-localization of microbat IFITM3 to Golgi-associated sites. Thus, we propose that S-palmitoylation is critical for Chiropteran IFITM3 function and identify a key molecular determinant of IFITM3 S-palmitoylation.

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• Journal article
  Kryza T, Bock N, Lovell S, Rockstroh A, Lehman ML, Lesner A, Panchadsaram J, Silva LM, Srinivasan S, Snell CE, Williams ED, Fazli L, Gleave M, Batra J, Nelson C, Tate EW, Harris J, Hooper JD, Clements JAet al., 2020,

  The molecular function of kallikrein-related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer

  , Molecular Oncology, Vol: 14, Pages: 105-128, ISSN: 1574-7891

  Kallikrein-related peptidase 14 (KLK14) is one of several secreted KLK serine proteases involved in prostate cancer (PCa) pathogenesis. While relatively understudied, recent reports have identified KLK14 as overexpressed during PCa development. However, the modulation of KLK14 expression during PCa progression and the molecular and biological functions of this protease in the prostate tumour microenvironment remain unknown. To determine the modulation of KLK14 expression during PCa progression, we analysed the expression levels of KLK14 in patient samples using publicly available databases and immunohistochemistry. In order to delineate the molecular mechanisms involving KLK14 in PCa progression, we integrated proteomic, transcriptomic and in vitro assays with the goal to identify substrates, related-signalling pathways and functional roles of this protease. We showed that KLK14 expression is elevated in advanced PCa, and particularly in metastasis. Additionally, KLK14 levels were found to be decreased in PCa tissues from patients responsive to neo-adjuvant therapy compared to untreated patients. Furthermore, we also identified that KLK14 expression re-occurred in patients who developed castrate-resistant PCa. The combination of proteomic and transcriptomic analysis as well as functional assays revealed several new KLK14-substrates (agrin, desmoglein 2, vitronectin, laminins) and KLK14-regulated genes (Interleukin 32, midkine, Sox9), particularly an involvement of the MAPK1 and IL1RN pathways, and an involvement of KLK14 in the regulation of cellular migration, supporting its involvement in aggressive features of PCa progression. In conclusion, our work showed that KLK14 expression is associated with the development of aggressive PCa suggesting that targeting this protease could offer a novel route to limit the progression of prostate tumours. Additional work is necessary to determine the benefits and implications of targeting/co-targeting KLK14 in PCa as well as to

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