Cooperative Heparin-Mediated Oligomerization of Fibroblast Growth Factor-1 (FGF1) Precedes Recruitment of FGFR2 to Ternary Complexes.
Biophys J. 2013 Apr 16;104(8):1720-30
Authors: Brown A, Robinson CJ, Gallagher JT, Blundell TL
Fibroblast growth factors (FGFs) utilize cell surface heparan sulfate as a coreceptor in the assembly of signaling complexes with FGF-receptors on the plasma membrane. Here we undertake a complete thermodynamic characterization of the assembly of the FGF signaling complex using isothermal titration calorimetry. Heparin fragments of defined length are used as chemical analogs of the sulfated domains of heparan sulfate and examined for their ability to oligomerize FGF1. Binding is modeled using the McGhee-von Hippel formalism for the cooperative binding of ligands to a monodimensional lattice. Oligomerization of FGFs on heparin is shown to be mediated by positive cooperativity (α = 6). Heparin octasaccharide is the shortest length capable of dimerizing FGF1 and on longer heparin chains FGF1 binds with a minimal footprint of 4.2 saccharide units. The thermodynamics and stoichiometry of the ternary complex suggest that in solution FGF1 binds to heparin in a trans-dimeric manner before FGFR recruitment.
PMID: 23601319 [PubMed - in process]
Molecular Mechanism of SSR128129E, an Extracellularly Acting, Small-Molecule, Allosteric Inhibitor of FGF Receptor Signaling.
Cancer Cell. 2013 Apr 15;23(4):489-501
Authors: Herbert C, Schieborr U, Saxena K, Juraszek J, De Smet F, Alcouffe C, Bianciotto M, Saladino G, Sibrac D, Kudlinzki D, Sreeramulu S, Brown A, Rigon P, Herault JP, Lassalle G, Blundell TL, Rousseau F, Gils A, Schymkowitz J, Tompa P, Herbert JM, Carmeliet P, Gervasio FL, Schwalbe H, Bono F
The fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling network plays an important role in cell growth, survival, differentiation, and angiogenesis. Deregulation of FGFR signaling can lead to cancer development. Here, we report an FGFR inhibitor, SSR128129E (SSR), that binds to the extracellular part of the receptor. SSR does not compete with FGF for binding to FGFR but inhibits FGF-induced signaling linked to FGFR internalization in an allosteric manner, as shown by crystallography studies, nuclear magnetic resonance, Fourier transform infrared spectroscopy, molecular dynamics simulations, free energy calculations, structure-activity relationship analysis, and FGFR mutagenesis. Overall, SSR is a small molecule allosteric inhibitor of FGF/FGFR signaling, acting via binding to the extracellular part of the FGFR.
PMID: 23597563 [PubMed - as supplied by publisher]
Structure of the Catalytic Region of DNA Ligase IV in Complex with an Artemis Fragment Sheds Light on Double-Strand Break Repair.
Structure. 2013 Mar 20;
Authors: Ochi T, Gu X, Blundell TL
Nonhomologous end joining (NHEJ) is central to the repair of double-stranded DNA breaks throughout the cell cycle and plays roles in the development of the immune system. Although three-dimensional structures of most components of NHEJ have been defined, those of the catalytic region of DNA ligase IV (LigIV), a specialized DNA ligase known to work in NHEJ, and of Artemis have remained unresolved. Here, we report the crystal structure at 2.4 Å resolution of the catalytic region of LigIV (residues 1-609) in complex with an Artemis peptide. We describe interactions of the DNA-binding domain of LigIV with the continuous epitope of Artemis, which, together, form a three-helix bundle. A kink in the first helix of LigIV introduced by a conserved VPF motif gives rise to a hydrophobic pocket, which accommodates a conserved tryptophan from Artemis. We provide structural insights into features of LigIV among human DNA ligases.
PMID: 23523427 [PubMed - as supplied by publisher]
Professor Dame Louise Napier Johnson (26 September 1940-25 September 2012).
Acta Crystallogr D Biol Crystallogr. 2012 Nov;68(Pt 11):1588-90
Authors: Blundell TL
PMID: 23090409 [PubMed - indexed for MEDLINE]