Imperial College London

Prof Ed Tate

Faculty of Natural SciencesDepartment of Chemistry

Professor of Chemical Biology
 
 
 
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Contact

 

+44 (0)20 7594 3752e.tate Website CV

 
 
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Assistant

 

Ms Agnes Lee +44 (0)20 7594 9852

 
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Location

 

639ChemistrySouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

125 results found

Beard R, Stucki A, Schmitt M, Py G, Grundschober C, Gee AD, Tate EWet al., 2018, Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs., Bioorg Med Chem

Oxytocin (OT) is an exciting potential therapeutic agent, but it is highly sensitive to modification and suffers extensive degradation at elevated temperature and in vivo. Here we report studies towards OT analogs with favorable selectivity, affinity and potency towards the oxytocin receptor (OTR), in addition to improving stability of the peptide by bridging the disulfide region with substituted dibromo-xylene analogs. We found a sensitive structure-activity relationship in which meta-cyclized analogs (dOTmeta) gave highest affinity (50 nM Ki), selectivity (34-fold), and agonist potency (34 nM EC50, 87-fold selectivity) towards OTR. Surprisingly, ortho-cyclized analogs demonstrated OTR and vasopressin V1areceptor subtype affinity (220 nM and 69 nM, respectively) and pharmacological activity (294 nM and 35 nM, respectively). V1abinding and selectivity for ortho-cyclized peptides could be improved 6-fold by substituting a neutral residue at position 8 with a basic amino acid, providing potent antagonists (14 nM IC50) that displayed no activation of the OTR. Furthermore, xylene-bridged analogs demonstrated increased stability compared to OT at elevated temperature, demonstrating promising therapeutic potential for these analogs which warrants further study.

JOURNAL ARTICLE

Craven GB, Affron DP, Allen CE, Matthies S, Greener JG, Morgan RML, Tate EW, Armstrong A, Mann DJet al., 2018, High-Throughput Kinetic Analysis for Target-Directed Covalent Ligand Discovery., Angew Chem Int Ed Engl

Cysteine-reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high-quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan-reactive compounds. Quantitative irreversible tethering (qIT), a general method for screening cysteine-reactive small molecules based upon the maximization of kinetic selectivity, is described. This method was applied prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2-selective allosteric (type IV) kinase inhibitor whose novel mode-of-action could be exploited therapeutically.

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Lubin AS, Rueda-Zubiaurre A, Matthews H, Baumann H, Fisher FR, Morales-Sanfrutos J, Hadavizadeh KS, Nardella F, Tate EW, Baum J, Scherf A, Fuchter MJet al., 2018, Development of a Photo-Cross-Linkable Diaminoquinazoline Inhibitor for Target Identification in Plasmodium falciparum., ACS Infect Dis

Diaminoquinazolines represent a privileged scaffold for antimalarial discovery, including use as putative Plasmodium histone lysine methyltransferase inhibitors. Despite this, robust evidence for their molecular targets is lacking. Here we report the design and development of a small-molecule photo-cross-linkable probe to investigate the targets of our diaminoquinazoline series. We demonstrate the effectiveness of our designed probe for photoaffinity labeling of Plasmodium lysates and identify similarities between the target profiles of the probe and the representative diaminoquinazoline BIX-01294. Initial pull-down proteomics experiments identified 104 proteins from different classes, many of which are essential, highlighting the suitability of the developed probe as a valuable tool for target identification in Plasmodium falciparum.

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Pollard DJ, Berger CN, So EC, Yu L, Hadavizadeh K, Jennings P, Tate EW, Choudhary JS, Frankel Get al., 2018, Broad-Spectrum Regulation of Nonreceptor Tyrosine Kinases by the Bacterial ADP-Ribosyltransferase EspJ., MBio, Vol: 9

Tyrosine phosphorylation is key for signal transduction from exogenous stimuli, including the defense against pathogens. Conversely, pathogens can subvert protein phosphorylation to control host immune responses and facilitate invasion and dissemination. The bacterial effectors EspJ and SeoC are injected into host cells through a type III secretion system by enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively), Citrobacter rodentium, and Salmonella enterica, where they inhibit Src kinase by coupled amidation and ADP-ribosylation. C. rodentium, which is used to model EPEC and EHEC infections in humans, is a mouse pathogen triggering colonic crypt hyperplasia (CCH) and colitis. Enumeration of bacterial shedding and CCH confirmed that EspJ affects neither tolerance nor resistance to infection. However, comparison of the proteomes of intestinal epithelial cells isolated from mice infected with wild-type C. rodentium or C. rodentium encoding catalytically inactive EspJ revealed that EspJ-induced ADP-ribosylation regulates multiple nonreceptor tyrosine kinases in vivo Investigation of the substrate repertoire of EspJ revealed that in HeLa and A549 cells, Src and Csk were significantly targeted; in polarized Caco2 cells, EspJ targeted Src and Csk and the Src family kinase (SFK) Yes1, while in differentiated Thp1 cells, EspJ modified Csk, the SFKs Hck and Lyn, the Tec family kinases Tec and Btk, and the adapter tyrosine kinase Syk. Furthermore, Abl (HeLa and Caco2) and Lyn (Caco2) were enriched specifically in the EspJ-containing samples. Biochemical assays revealed that EspJ, the only bacterial ADP-ribosyltransferase that targets mammalian kinases, controls immune responses and the Src/Csk signaling axis.IMPORTANCE Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively) strains cause significant mortality and morbidity worldwide. Citrobacter rodentium is a mouse pathogen used to model EPEC and EHEC pathogenesis

JOURNAL ARTICLE

Ritzefeld M, Wright MH, Tate EW, 2018, New developments in probing and targeting protein acylation in malaria, leishmaniasis and African sleeping sickness, PARASITOLOGY, Vol: 145, Pages: 157-174, ISSN: 0031-1820

JOURNAL ARTICLE

Schlott AC, Holder AA, Tate EW, 2018, N-Myristoylation as a Drug Target in Malaria: Exploring the Role of N-Myristoyltransferase Substrates in the Inhibitor Mode of Action., ACS Infect Dis

Malaria continues to be a significant cause of death and morbidity worldwide, and there is a need for new antimalarial drugs with novel targets. We have focused as a potential target for drug development on N-myristoyl transferase (NMT), an enzyme that acylates a wide range of substrate proteins. The NMT substrates in Plasmodium falciparum include some proteins that are common to processes in eukaryotes such as secretory transport and others that are unique to apicomplexan parasites. Myristoylation facilitates a protein interaction with membranes that may be strengthened by further lipidation, and the inhibition of NMT results in incorrect protein localization and the consequent disruption of function. The diverse roles of NMT substrates mean that NMT inhibition has a pleiotropic and severe impact on parasite development, growth, and multiplication. To study the mode of action underlying NMT inhibition, it is important to consider the function of proteins upstream and downstream of NMT. In this work, we therefore present our current perspective on the different functions of known NMT substrates as well as compare the inhibition of cotranslational myristoylation to the inhibition of known targets upstream of NMT.

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Clulow JA, Storck EM, Lanyon-Hogg T, Kalesh KA, Jones LH, Tate EWet al., 2017, Competition-based, quantitative chemical proteomics in breast cancer cells identifies new target profiles for sulforaphane, CHEMICAL COMMUNICATIONS, Vol: 53, Pages: 5182-5185, ISSN: 1359-7345

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Demetriadou A, Morales-Sanfrutos J, Nearchou M, Baba O, Kyriacou K, Tate EW, Drousiotou A, Petrou PPet al., 2017, Mouse Stbd1 is N-myristoylated and affects ER-mitochondria association and mitochondrial morphology, JOURNAL OF CELL SCIENCE, Vol: 130, Pages: 903-915, ISSN: 0021-9533

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Duluc L, Ahmetaj-Shala B, Mitchell J, Abdul-Salam VB, Mahomed AS, Aldabbous L, Oliver E, Iannone L, Dubois OD, Storck EM, Tate EW, Zhao L, Wilkins MR, Wojciak-Stothard Bet al., 2017, Tipifarnib prevents development of hypoxia-induced pulmonary hypertension, CARDIOVASCULAR RESEARCH, Vol: 113, Pages: 276-287, ISSN: 0008-6363

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Gorlitz F, Kelly DJ, Warren SC, Alibhai D, West L, Kumar S, Alexandrov Y, Munro I, Garcia E, McGinty J, Talbot C, Serwa RA, Thinon E, da Paola V, Murray EJ, Stuhmeier F, Neil MAA, Tate EW, Dunsby C, French PMWet al., 2017, Open Source High Content Analysis Utilizing Automated Fluorescence Lifetime Imaging Microscopy, JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, ISSN: 1940-087X

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Lanyon-Hogg T, Faronato M, Serwa RA, Tate EWet al., 2017, Dynamic protein acylation: new substrates, mechanisms and drug targets, Trends in Biochemical Sciences, Vol: 42, Pages: 566-581, ISSN: 0968-0004

Post-translational attachment of lipids to proteins is found in all organisms, and is important for many biological processes. Acylation with myristic and palmitic acids are among the most common lipid modifications, and understanding reversible protein palmitoylation dynamics has become a particularly important goal. Linking acyltransferase enzymes to disease states can be challenging due to a paucity of robust models, compounded by functional redundancy between many palmitoyl transferases; however, in cases such as Wnt or Hedgehog signalling, small molecule inhibitors have been identified, with some progressing to clinical trials. In this review, we present recent developments in our understanding of protein acylation in human health and disease through use of chemical tools, global profiling of acylated proteomes, and functional studies of specific protein targets.

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Lanyon-Hogg T, Patel NV, Ritzefeld M, Boxall KJ, Burke R, Blagg J, Magee AI, Tate EWet al., 2017, Microfluidic Mobility Shift Assay for Real-Time Analysis of Peptide N-Palmitoylation, SLAS DISCOVERY, Vol: 22, Pages: 418-424, ISSN: 2472-5552

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Perdios L, Lowe AR, Saladino G, Bunney TD, Thiyagarajan N, Alexandrov Y, Dunsby C, French PMW, Chin JW, Gervasio FL, Tate EW, Katan Met al., 2017, Conformational transition of FGFR kinase activation revealed by site-specific unnatural amino acid reporter and single molecule FRET, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322

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Zhao W, Jamshidiha M, Lanyon-Hogg T, Recchi C, Cota E, Tate EWet al., 2017, Direct Targeting of the Ras GTPase Superfamily Through Structure-Based Design, CURRENT TOPICS IN MEDICINAL CHEMISTRY, Vol: 17, Pages: 16-29, ISSN: 1568-0266

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Albrow VE, Grimley RL, Clulow J, Rose CR, Sun J, Warmus JS, Tate EW, Jones LH, Storer RIet al., 2016, Design and development of histone deacetylase (HDAC) chemical probes for cell-based profiling, MOLECULAR BIOSYSTEMS, Vol: 12, Pages: 1781-1789, ISSN: 1742-206X

JOURNAL ARTICLE

Broncel M, Serwa RA, Bunney TD, Katan M, Tate EWet al., 2016, Global Profiling of Huntingtin-associated protein E (HYPE)-Mediated AMPylation through a Chemical Proteomic Approach, MOLECULAR & CELLULAR PROTEOMICS, Vol: 15, Pages: 715-725, ISSN: 1535-9476

JOURNAL ARTICLE

Goncalves V, Brannigan JA, Laporte A, Bell AS, Roberts SM, Wilkinson AJ, Leatherbarrow RJ, Tate EWet al., 2016, Structure-guided optimization of quinoline inhibitors of Plasmodium N-myristoyltransferase, MedChemComm, Vol: 8, Pages: 191-197, ISSN: 2040-2511

The parasite Plasmodium vivax is the most widely distributed cause of recurring malaria. N-myristoyltransferase (NMT), an enzyme that catalyses the covalent attachment of myristate to the N-terminal glycine of substrate proteins, has been described as a potential target for the treatment of this disease. Herein, we report the synthesis and the structure-guided optimization of a series of quinolines with balanced activity against both Plasmodium vivax and Plasmodium falciparum N-myristoyltransferase (NMT).

JOURNAL ARTICLE

Lanyon-Hogg T, Masumoto N, Bodakh G, Konitsiotis AD, Thinon E, Rodgers UR, Owens RJ, Magee AI, Tate EWet al., 2016, Synthesis and characterisation of 5-acyl-6,7-dihydrothieno[3,2-c]pyridine inhibitors of Hedgehog acyltransferase., Data Brief, Vol: 7, Pages: 257-281, ISSN: 2352-3409

In this data article we describe synthetic and characterisation data for four members of the 5-acyl-6,7-dihydrothieno[3,2-c]pyridine (termed "RU-SKI") class of inhibitors of Hedgehog acyltransferase, including associated NMR spectra for final compounds. RU-SKI compounds were selected for synthesis based on their published high potencies against the enzyme target. RU-SKI 41 (9a), RU-SKI 43 (9b), RU-SKI 101 (9c), and RU-SKI 201 (9d) were profiled for activity in the related article "Click chemistry armed enzyme linked immunosorbent assay to measure palmitoylation by Hedgehog acyltransferase" (Lanyon-Hogg et al., 2015) [1]. (1)H NMR spectral data indicate different amide conformational ratios between the RU-SKI inhibitors, as has been observed in other 5-acyl-6,7-dihydrothieno[3,2-c]pyridines. The synthetic and characterisation data supplied in the current article provide validated access to the class of RU-SKI inhibitors.

JOURNAL ARTICLE

Perdios L, Bunney TD, Warren SC, Dunsby C, French PMW, Tate EW, Katan Met al., 2016, Time-resolved FRET reports FGFR1 dimerization and formation of a complex with its effector PLCγ1., Adv Biol Regul, Vol: 60, Pages: 6-13

In vitro and in vivo imaging of protein tyrosine kinase activity requires minimally invasive, molecularly precise optical probes to provide spatiotemporal mechanistic information of dimerization and complex formation with downstream effectors. We present here a construct with genetically encoded, site-specifically incorporated, bioorthogonal reporter that can be selectively labelled with exogenous fluorogenic probes to monitor the structure and function of fibroblast growth factor receptor (FGFR). GyrB.FGFR1KD.TC contains a coumermycin-induced artificial dimerizer (GyrB), FGFR1 kinase domain (KD) and a tetracysteine (TC) motif that enables fluorescent labelling with biarsenical dyes FlAsH-EDT2 and ReAsH-EDT2. We generated bimolecular system for time-resolved FRET (TR-FRET) studies, which pairs FlAsH-tagged GyrB.FGFR1KD.TC and N-terminal Src homology 2 (nSH2) domain of phospholipase Cγ (PLCγ), a downstream effector of FGFR1, fused to mTurquoise fluorescent protein (mTFP). We demonstrated phosphorylation-dependent TR-FRET readout of complex formation between mTFP.nSH2 and GyrB.FGFR1KD.TC. By further application of TR-FRET, we also demonstrated formation of the GyrB.FGFR1KD.TC homodimer by coumermycin-induced dimerization. Herein, we present a spectroscopic FRET approach to facilitate and propagate studies that would provide structural and functional insights for FGFR and other tyrosine kinases.

JOURNAL ARTICLE

Rodgers UR, Lanyon-Hogg T, Masumoto N, Ritzefeld M, Burke R, Blagg J, Magee AI, Tate EWet al., 2016, Characterization of Hedgehog Acyltransferase Inhibitors Identifies a Small Molecule Probe for Hedgehog Signaling by Cancer Cells, ACS CHEMICAL BIOLOGY, Vol: 11, Pages: 3256-3262, ISSN: 1554-8929

JOURNAL ARTICLE

So EC, Schroeder GN, Carson D, Mattheis C, Mousnier A, Broncel M, Tate EW, Frankel Get al., 2016, The Rab-binding Profiles of Bacterial Virulence Factors during Infection, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 291, Pages: 5832-5843, ISSN: 0021-9258

JOURNAL ARTICLE

Thinon E, Morales-Sanfrutos J, Mann DJ, Tate EWet al., 2016, N-Myristoyltransferase Inhibition Induces ER-Stress, Cell Cycle Arrest, and Apoptosis in Cancer Cells, ACS CHEMICAL BIOLOGY, Vol: 11, Pages: 2165-2176, ISSN: 1554-8929

JOURNAL ARTICLE

Ward JA, McLellan L, Stockley M, Gibson KR, Whitlock GA, Knights C, Harrigan JA, Jacq X, Tate EWet al., 2016, Quantitative Chemical Proteomic Profiling of Ubiquitin Specific Proteases in Intact Cancer Cells, ACS CHEMICAL BIOLOGY, Vol: 11, Pages: 3268-3272, ISSN: 1554-8929

JOURNAL ARTICLE

Wright MH, Paape D, Price HP, Smith DF, Tate EWet al., 2016, Global Profiling and Inhibition of Protein Lipidation in Vector and Host Stages of the Sleeping Sickness Parasite Trypanosoma brucei, ACS INFECTIOUS DISEASES, Vol: 2, Pages: 427-441, ISSN: 2373-8227

JOURNAL ARTICLE

Broncel M, Serwa RA, Ciepla P, Krause E, Dallman MJ, Magee AI, Tate EWet al., 2015, Multifunctional Reagents for Quantitative Proteome-Wide Analysis of Protein Modification in Human Cells and Dynamic Profiling of Protein Lipidation During Vertebrate Development, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 54, Pages: 5948-5951, ISSN: 1433-7851

JOURNAL ARTICLE

Broncel M, Serwa RA, Ciepla P, Krause E, Dallman MJ, Magee AI, Tate EWet al., 2015, Myristoylation profiling in human cells and zebrafish., Data Brief, Vol: 4, Pages: 379-383, ISSN: 2352-3409

Human cells (HEK 293, HeLa, MCF-7) and zebrafish embryos were metabolically tagged with an alkynyl myristic acid probe, lysed with an SDS buffer and tagged proteomes ligated to multifunctional capture reagents via copper-catalyzed alkyne azide cycloaddition (CuAAC). This allowed for affinity enrichment and high-confidence identification, by delivering direct MS/MS evidence for the modification site, of 87 and 61 co-translationally myristoylated proteins in human cells and zebrafish, respectively. The data have been deposited to ProteomeXchange Consortium (Vizcaíno et al., 2014 Nat. Biotechnol., 32, 223-6) (PXD001863 and PXD001876) and are described in detail in Multifunctional reagents for quantitative proteome-wide analysis of protein modification in human cells and dynamic protein lipidation during vertebrate development׳ by Broncel et al., Angew. Chem. Int. Ed.

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Charlton TM, Kovacs-Simon A, Michell SL, Fairweather NF, Tate EWet al., 2015, Quantitative Lipoproteomics in Clostridium difficile Reveals a Role for Lipoproteins in Sporulation, CHEMISTRY & BIOLOGY, Vol: 22, Pages: 1562-1573, ISSN: 1074-5521

JOURNAL ARTICLE

Ciepla P, Magee AI, Tate EW, 2015, Cholesterylation: a tail of hedgehog, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 43, Pages: 262-267, ISSN: 0300-5127

JOURNAL ARTICLE

Douse CH, Vrielink N, Zhang W, Cota E, Tate EWet al., 2015, Targeting a Dynamic Protein-Protein Interaction: Fragment Screening against the Malaria Myosin A Motor Complex, CHEMMEDCHEM, Vol: 10, Pages: 134-143, ISSN: 1860-7179

JOURNAL ARTICLE

Furse S, Mak L, Tate EW, Templer RH, Ces O, Woscholski R, Gaffney PRJet al., 2015, Synthesis of unsaturated phosphatidylinositol 4-phosphates and the effects of substrate unsaturation on SopB phosphatase activity, ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 13, Pages: 2001-2011, ISSN: 1477-0520

JOURNAL ARTICLE

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