Now showing items 29-48 of 91

    • 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 ...
    • A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms. 

      Jones, AM; Westwood, IM; Osborne, JD; Matthews, TP; Cheeseman, MD; Rowlands, MG; Jeganathan, F; Burke, R; Lee, D; Kadi, N; Liu, M; Richards, M; McAndrew, C; Yahya, N; Dobson, SE; Jones, K; Workman, P; Collins, I; van Montfort, RLM (2016-10-06)
      The heat shock protein 70s (HSP70s) are molecular chaperones implicated in many cancers and of significant interest as targets for novel cancer therapies. Several HSP70 inhibitors have been reported, but because the majority ...
    • Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase. 

      Pollock, K; Liu, M; Zaleska, M; Meniconi, M; Pfuhl, M; Collins, I; Guettler, S (2019-12-13)
      The PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A number of these are implicated in ...
    • Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. 

      Pettitt, SJ; Krastev, DB; Brandsma, I; Dréan, A; Song, F; Aleksandrov, R; Harrell, MI; Menon, M; Brough, R; Campbell, J; Frankum, J; Ranes, M; Pemberton, HN; Rafiq, R; Fenwick, K; Swain, A; Guettler, S; Lee, J-M; Swisher, EM; Stoynov, S; Yusa, K; Ashworth, A; Lord, CJ (2018-05-10)
      Although PARP inhibitors (PARPi) target homologous recombination defective tumours, drug resistance frequently emerges, often via poorly understood mechanisms. Here, using genome-wide and high-density CRISPR-Cas9 ...
    • Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer. 

      Woolston, A; Khan, K; Spain, G; Barber, LJ; Griffiths, B; Gonzalez-Exposito, R; Hornsteiner, L; Punta, M; Patil, Y; Newey, A; Mansukhani, S; Davies, MN; Furness, A; Sclafani, F; Peckitt, C; Jiménez, M; Kouvelakis, K; Ranftl, R; Begum, R; Rana, I; Thomas, J; Bryant, A; Quezada, S; Wotherspoon, A; Khan, N; Fotiadis, N; Marafioti, T; Powles, T; Lise, S; Calvo, F; Guettler, S; von Loga, K; Rao, S; Watkins, D; Starling, N; Chau, I; Sadanandam, A; Cunningham, D; Gerlinger, M (2019-07)
      Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS ...
    • High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers. 

      Anderhub, SJ; Mak, GW-Y; Gurden, MD; Faisal, A; Drosopoulos, K; Walsh, K; Woodward, HL; Innocenti, P; Westwood, IM; Naud, S; Hayes, A; Theofani, E; Filosto, S; Saville, H; Burke, R; van Montfort, RLM; Raynaud, FI; Blagg, J; Hoelder, S; Eccles, SA; Linardopoulos, S (2019-10)
      BOS172722 (CCT289346) is a highly potent, selective, and orally bioavailable inhibitor of spindle assembly checkpoint kinase MPS1. BOS172722 treatment alone induces significant sensitization to death, particularly in highly ...
    • High-resolution cryo-EM proteasome structures in drug development. 

      Morris, EP; da Fonseca, PCA (2017-06)
      With the recent advances in biological structural electron microscopy (EM), protein structures can now be obtained by cryo-EM and single-particle analysis at resolutions that used to be achievable only by crystallographic ...
    • Human Condensin I and II Drive Extensive ATP-Dependent Compaction of Nucleosome-Bound DNA. 

      Kong, M; Cutts, EE; Pan, D; Beuron, F; Kaliyappan, T; Xue, C; Morris, EP; Musacchio, A; Vannini, A; Greene, EC (2020-07)
      Structural maintenance of chromosomes (SMC) complexes are essential for genome organization from bacteria to humans, but their mechanisms of action remain poorly understood. Here, we characterize human SMC complexes condensin ...
    • Hybrid Gene Origination Creates Human-Virus Chimeric Proteins during Infection. 

      Ho, JSY; Angel, M; Ma, Y; Sloan, E; Wang, G; Martinez-Romero, C; Alenquer, M; Roudko, V; Chung, L; Zheng, S; Chang, M; Fstkchyan, Y; Clohisey, S; Dinan, AM; Gibbs, J; Gifford, R; Shen, R; Gu, Q; Irigoyen, N; Campisi, L; Huang, C; Zhao, N; Jones, JD; van Knippenberg, I; Zhu, Z; Moshkina, N; Meyer, L; Noel, J; Peralta, Z; Rezelj, V; Kaake, R; Rosenberg, B; Wang, B; Wei, J; Paessler, S; Wise, HM; Johnson, J; Vannini, A; Amorim, MJ; Baillie, JK; Miraldi, ER; Benner, C; Brierley, I; Digard, P; Łuksza, M; Firth, AE; Krogan, N; Greenbaum, BD; MacLeod, MK; van Bakel, H; Garcìa-Sastre, A; Yewdell, JW; Hutchinson, E; Marazzi, I (2020-06-18)
      RNA viruses are a major human health threat. The life cycles of many highly pathogenic RNA viruses like influenza A virus (IAV) and Lassa virus depends on host mRNA, because viral polymerases cleave 5'-m7G-capped host ...
    • Identifying and Validating Tankyrase Binders and Substrates: A Candidate Approach. 

      Pollock, K; Ranes, M; Collins, I; Guettler, S (2017-01)
      The poly(ADP-ribose)polymerase (PARP) enzyme tankyrase (TNKS/ARTD5, TNKS2/ARTD6) uses its ankyrin repeat clusters (ARCs) to recognize degenerate peptide motifs in a wide range of proteins, thereby recruiting such proteins ...
    • Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors. 

      Vaughan, L; Clarke, PA; Barker, K; Chanthery, Y; Gustafson, CW; Tucker, E; Renshaw, J; Raynaud, F; Li, X; Burke, R; Jamin, Y; Robinson, SP; Pearson, A; Maira, M; Weiss, WA; Workman, P; Chesler, L (2016-09)
      MYC oncoproteins deliver a potent oncogenic stimulus in several human cancers, making them major targets for drug development, but efforts to deliver clinically practical therapeutics have not yet been realized. In childhood ...
    • The Interacting Head Motif Structure Does Not Explain the X-Ray Diffraction Patterns in Relaxed Vertebrate (Bony Fish) Skeletal Muscle and Insect (<i>Lethocerus</i>) Flight Muscle. 

      Knupp, C; Morris, E; Squire, JM (2019-09-14)
      Unlike electron microscopy, which can achieve very high resolution but to date can only be used to study static structures, time-resolved X-ray diffraction from contracting muscles can, in principle, be used to follow the ...
    • Investigating the phosphinic acid tripeptide mimetic DG013A as a tool compound inhibitor of the M1-aminopeptidase ERAP1. 

      Wilding, B; Pasqua, AE; E A Chessum, N; Pierrat, OA; Hahner, T; Tomlin, K; Shehu, E; Burke, R; Richards, GM; Whitton, B; Arwert, EN; Thapaliya, A; Salimraj, R; van Montfort, R; Skawinska, A; Hayes, A; Raynaud, F; Chopra, R; Jones, K; Newton, G; Cheeseman, MD
      ERAP1 is a zinc-dependent M1-aminopeptidase that trims lipophilic amino acids from the N-terminus of peptides. Owing to its importance in the processing of antigens and regulation of the adaptive immune response, dysregulation ...
    • An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine-56. 

      Pettinger, J; Le Bihan, Y-V; Widya, M; van Montfort, RLM; Jones, K; Cheeseman, MD (2017-03)
      The stress-inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells ...
    • Large Stokes shift fluorescence activation in an RNA aptamer by intermolecular proton transfer to guanine. 

      Mieczkowski, M; Steinmetzger, C; Bessi, I; Lenz, A-K; Schmiedel, A; Holzapfel, M; Lambert, C; Pena, V; Höbartner, C (2021-06-10)
      Fluorogenic RNA aptamers are synthetic functional RNAs that specifically bind and activate conditional fluorophores. The Chili RNA aptamer mimics large Stokes shift fluorescent proteins and exhibits high affinity for ...
    • Mechanism for remodelling of the cell cycle checkpoint protein MAD2 by the ATPase TRIP13. 

      Alfieri, C; Chang, L; Barford, D (2018-07-04)
      The maintenance of genome stability during mitosis is coordinated by the spindle assembly checkpoint (SAC) through its effector the mitotic checkpoint complex (MCC), an inhibitor of the anaphase-promoting complex (APC/C, ...
    • Mechanism of selective recruitment of RNA polymerases II and III to snRNA gene promoters. 

      Dergai, O; Cousin, P; Gouge, J; Satia, K; Praz, V; Kuhlman, T; Lhôte, P; Vannini, A; Hernandez, N (2018-05-21)
      RNA polymerase II (Pol II) small nuclear RNA (snRNA) promoters and type 3 Pol III promoters have highly similar structures; both contain an interchangeable enhancer and "proximal sequence element" (PSE), which recruits the ...
    • MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma. 

      Lampis, A; Carotenuto, P; Vlachogiannis, G; Cascione, L; Hedayat, S; Burke, R; Clarke, P; Bosma, E; Simbolo, M; Scarpa, A; Yu, S; Cole, R; Smyth, E; Mateos, JF; Begum, R; Hezelova, B; Eltahir, Z; Wotherspoon, A; Fotiadis, N; Bali, MA; Nepal, C; Khan, K; Stubbs, M; Hahne, JC; Gasparini, P; Guzzardo, V; Croce, CM; Eccles, S; Fassan, M; Cunningham, D; Andersen, JB; Workman, P; Valeri, N; Braconi, C (2018-03)
      BACKGROUND & AIMS:Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small-molecule compounds that are active against CCAs. Levels of microRNA ...
    • MOB1 Mediated Phospho-recognition in the Core Mammalian Hippo Pathway. 

      Couzens, AL; Xiong, S; Knight, JDR; Mao, DY; Guettler, S; Picaud, S; Kurinov, I; Filippakopoulos, P; Sicheri, F; Gingras, A-C (2017-06)
      The Hippo tumor suppressor pathway regulates organ size and tissue homoeostasis in response to diverse signaling inputs. The core of the pathway consists of a short kinase cascade: MST1 and MST2 phosphorylate and activate ...
    • Molecular basis of APC/C regulation by the spindle assembly checkpoint. 

      Alfieri, C; Chang, L; Zhang, Z; Yang, J; Maslen, S; Skehel, M; Barford, D (2016-08-10)
      In the dividing eukaryotic cell, the spindle assembly checkpoint (SAC) ensures that each daughter cell inherits an identical set of chromosomes. The SAC coordinates the correct attachment of sister chromatid kinetochores ...