Now showing items 1-20 of 82

    • Calmodulin-independent, agonistic properties of a peptide containing the calmodulin binding site of estrogen receptor alpha 

      Rowlands, Martin (2007-03-30)
      Calmodulin (CaM) contributes to estrogen receptor alpha (ER)-mediated transcription. In order to study the underlying mechanisms, we synthesized a peptide including the CaM binding site: ERalpha17p (P(295)-T(311)). This ...
    • Three-dimensional structure of recombinant type 1 inositol 1,4,5-trisphosphate receptor. 

      Wolfram, F; Morris, E; Taylor, CW (2010-05-27)
      IP3Rs (inositol 1,4,5-trisphosphate receptors) are the intracellular channels that mediate release of Ca2+ from the endoplasmic reticulum in response to the many stimuli that evoke Ins(1,4,5)P3 formation. We characterized ...
    • Structures of APC/C(Cdh1) with substrates identify Cdh1 and Apc10 as the D-box co-receptor. 

      da Fonseca, PCA; Kong, EH; Zhang, Z; Schreiber, A; Williams, MA; Morris, EP; Barford, D (2011-02)
      The ubiquitylation of cell-cycle regulatory proteins by the large multimeric anaphase-promoting complex (APC/C) controls sister chromatid segregation and the exit from mitosis. Selection of APC/C targets is achieved through ...
    • Cnn1 inhibits the interactions between the KMN complexes of the yeast kinetochore. 

      Bock, LJ; Pagliuca, C; Kobayashi, N; Grove, RA; Oku, Y; Shrestha, K; Alfieri, C; Golfieri, C; Oldani, A; Dal Maschio, M; Bermejo, R; Hazbun, TR; Tanaka, TU; De Wulf, P (2012-05-06)
      Kinetochores attach the replicated chromosomes to the mitotic spindle and orchestrate their transmission to the daughter cells. Kinetochore-spindle binding and chromosome segregation are mediated by the multi-copy KNL1(Spc105), ...
    • The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design. 

      Couty, S; Westwood, IM; Kalusa, A; Cano, C; Travers, J; Boxall, K; Chow, CL; Burns, S; Schmitt, J; Pickard, L; Barillari, C; McAndrew, PC; Clarke, PA; Linardopoulos, S; Griffin, RJ; Aherne, GW; Raynaud, FI; Workman, P; Jones, K; van Montfort, RLM (2013-10)
      The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we ...
    • Structural basis for translocation by AddAB helicase-nuclease and its arrest at χ sites. 

      Krajewski, WW; Fu, X; Wilkinson, M; Cronin, NB; Dillingham, MS; Wigley, DB (2014-04)
      In bacterial cells, processing of double-stranded DNA breaks for repair by homologous recombination is dependent upon the recombination hotspot sequence χ (Chi) and is catalysed by either an AddAB- or RecBCD-type ...
    • RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association. 

      Goodman, KM; Kjær, S; Beuron, F; Knowles, PP; Nawrotek, A; Burns, EM; Purkiss, AG; George, R; Santoro, M; Morris, EP; McDonald, NQ (2014-09-18)
      The RET receptor tyrosine kinase is essential to vertebrate development and implicated in multiple human diseases. RET binds a cell surface bipartite ligand comprising a GDNF family ligand and a GFRα coreceptor, resulting ...
    • SF3B1 mutations constitute a novel therapeutic target in breast cancer. 

      Maguire, SL; Leonidou, A; Wai, P; Marchiò, C; Ng, CK; Sapino, A; Salomon, A-V; Reis-Filho, JS; Weigelt, B; Natrajan, RC (2015-03)
      Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in several tumour types including myelodysplastic syndromes, chronic lymphocytic leukaemia, uveal melanoma, ...
    • Molecular mechanisms of human IRE1 activation through dimerization and ligand binding. 

      Joshi, A; Newbatt, Y; McAndrew, PC; Stubbs, M; Burke, R; Richards, MW; Bhatia, C; Caldwell, JJ; McHardy, T; Collins, I; Bayliss, R (2015-05)
      IRE1 transduces the unfolded protein response by splicing XBP1 through its C-terminal cytoplasmic kinase-RNase region. IRE1 autophosphorylation is coupled to RNase activity through formation of a back-to-back dimer, although ...
    • Redox Signaling by the RNA Polymerase III TFIIB-Related Factor Brf2. 

      Gouge, J; Satia, K; Guthertz, N; Widya, M; Thompson, AJ; Cousin, P; Dergai, O; Hernandez, N; Vannini, A (2015-12)
      TFIIB-related factor 2 (Brf2) is a member of the family of TFIIB-like core transcription factors. Brf2 recruits RNA polymerase (Pol) III to type III gene-external promoters, including the U6 spliceosomal RNA and selenocysteine ...
    • Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19. 

      Mallinger, A; Schiemann, K; Rink, C; Stieber, F; Calderini, M; Crumpler, S; Stubbs, M; Adeniji-Popoola, O; Poeschke, O; Busch, M; Czodrowski, P; Musil, D; Schwarz, D; Ortiz-Ruiz, M-J; Schneider, R; Thai, C; Valenti, M; de Haven Brandon, A; Burke, R; Workman, P; Dale, T; Wienke, D; Clarke, PA; Esdar, C; Raynaud, FI; Eccles, SA; Rohdich, F; Blagg, J (2016-02)
      The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 ...
    • 8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors. 

      Bavetsias, V; Lanigan, RM; Ruda, GF; Atrash, B; McLaughlin, MG; Tumber, A; Mok, NY; Le Bihan, Y-V; Dempster, S; Boxall, KJ; Jeganathan, F; Hatch, SB; Savitsky, P; Velupillai, S; Krojer, T; England, KS; Sejberg, J; Thai, C; Donovan, A; Pal, A; Scozzafava, G; Bennett, JM; Kawamura, A; Johansson, C; Szykowska, A; Gileadi, C; Burgess-Brown, NA; von Delft, F; Oppermann, U; Walters, Z; Shipley, J; Raynaud, FI; Westaway, SM; Prinjha, RK; Fedorov, O; Burke, R; Schofield, CJ; Westwood, IM; Bountra, C; Müller, S; van Montfort, RLM; Brennan, PE; Blagg, J (2016-02)
      We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a ...
    • Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach. 

      Innocenti, P; Woodward, HL; Solanki, S; Naud, S; Westwood, IM; Cronin, N; Hayes, A; Roberts, J; Henley, AT; Baker, R; Faisal, A; Mak, GW-Y; Box, G; Valenti, M; De Haven Brandon, A; O'Fee, L; Saville, H; Schmitt, J; Matijssen, B; Burke, R; van Montfort, RLM; Raynaud, FI; Eccles, SA; Linardopoulos, S; Blagg, J; Hoelder, S (2016-04-07)
      Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily ...
    • A closed conformation of the Caenorhabditis elegans separase-securin complex. 

      Bachmann, G; Richards, MW; Winter, A; Beuron, F; Morris, E; Bayliss, R (2016-04-13)
      The protease separase plays a key role in sister chromatid disjunction and centriole disengagement. To maintain genomic stability, separase activity is strictly regulated by binding of an inhibitory protein, securin. Despite ...
    • Molecular mechanism of APC/C activation by mitotic phosphorylation. 

      Zhang, S; Chang, L; Alfieri, C; Zhang, Z; Yang, J; Maslen, S; Skehel, M; Barford, D (2016-05)
      In eukaryotes, the anaphase-promoting complex (APC/C, also known as the cyclosome) regulates the ubiquitin-dependent proteolysis of specific cell-cycle proteins to coordinate chromosome segregation in mitosis and entry ...
    • Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70. 

      Cheeseman, MD; Westwood, IM; Barbeau, O; Rowlands, M; Dobson, S; Jones, AM; Jeganathan, F; Burke, R; Kadi, N; Workman, P; Collins, I; van Montfort, RLM; Jones, K (2016-05-11)
      HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought ...
    • Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737). 

      Osborne, JD; Matthews, TP; McHardy, T; Proisy, N; Cheung, K-MJ; Lainchbury, M; Brown, N; Walton, MI; Eve, PD; Boxall, KJ; Hayes, A; Henley, AT; Valenti, MR; De Haven Brandon, AK; Box, G; Jamin, Y; Robinson, SP; Westwood, IM; van Montfort, RLM; Leonard, PM; Lamers, MBAC; Reader, JC; Aherne, GW; Raynaud, FI; Eccles, SA; Garrett, MD; Collins, I (2016-06)
      Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy ...
    • 2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19. 

      Mallinger, A; Schiemann, K; Rink, C; Sejberg, J; Honey, MA; Czodrowski, P; Stubbs, M; Poeschke, O; Busch, M; Schneider, R; Schwarz, D; Musil, D; Burke, R; Urbahns, K; Workman, P; Wienke, D; Clarke, PA; Raynaud, FI; Eccles, SA; Esdar, C; Rohdich, F; Blagg, J (2016-06)
      We demonstrate a designed scaffold-hop approach to the discovery of 2,8-disubstituted-1,6-naphthyridine- and 4,6-disubstituted-isoquinoline-based dual CDK8/19 ligands. Optimized compounds in both series exhibited rapid ...
    • Nanostructures from Synthetic Genetic Polymers. 

      Taylor, AI; Beuron, F; Peak-Chew, S-Y; Morris, EP; Herdewijn, P; Holliger, P (2016-06)
      Nanoscale objects of increasing complexity can be constructed from DNA or RNA. However, the scope of potential applications could be enhanced by expanding beyond the moderate chemical diversity of natural nucleic acids. ...
    • Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling. 

      Mariotti, L; Templeton, CM; Ranes, M; Paracuellos, P; Cronin, N; Beuron, F; Morris, E; Guettler, S (2016-08)
      The poly(ADP-ribose) polymerase (PARP) Tankyrase (TNKS and TNKS2) is paramount to Wnt-β-catenin signaling and a promising therapeutic target in Wnt-dependent cancers. The pool of active β-catenin is normally limited by ...