Publications

Virtual screening and X-ray crystallography Identify non-substrate analog inhibitors of Flavin-dependent Thymidylate Synthase.

Publications by the Blundell group - Tue, 20/09/2016 - 03:12
Related Articles

Virtual screening and X-ray crystallography Identify non-substrate analog inhibitors of Flavin-dependent Thymidylate Synthase.

J Med Chem. 2016 Sep 2;

Authors: Luciani R, Saxena P, Surade S, Santucci M, Venturelli A, Borsari C, Marverti G, Ponterini G, Ferrari S, Blundell TL, Costi MP

Abstract
Thymidylate synthase-X (ThyX) represents an attractive target for tuberculosis drug discovery. Herein, we selected 16 compounds through a virtual screening approach. We solved the first X-ray crystal structure of Thermatoga maritima ThyX in complex with a non-substrate analog inhibitor. Given the active site similarities between Mtb-ThyX and Tm-ThyX, our crystal structure paves the way for a structure-based design of novel antimycobacterial compounds. The 1H-imidazo[4,5-d]pyridazine was identified as scaffold for the development of Mtb-ThyX inhibitors.

PMID: 27589670 [PubMed - as supplied by publisher]

Categories: Publications

Molecular Mechanism of SSR128129E, an Extracellularly Acting, Small-Molecule, Allosteric Inhibitor of FGF Receptor Signaling.

Publications by the Blundell group - Tue, 30/08/2016 - 00:47

Molecular Mechanism of SSR128129E, an Extracellularly Acting, Small-Molecule, Allosteric Inhibitor of FGF Receptor Signaling.

Cancer Cell. 2016 Jul 11;30(1):176-178

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

PMID: 27479031 [PubMed - as supplied by publisher]

Categories: Publications

ATP half-sites in RadA and RAD51 recombinases bind nucleotides.

Publications by the Blundell group - Mon, 01/08/2016 - 13:42

ATP half-sites in RadA and RAD51 recombinases bind nucleotides.

FEBS Open Bio. 2016 May;6(5):372-85

Authors: Marsh ME, Scott DE, Ehebauer MT, Abell C, Blundell TL, Hyvönen M

Abstract
Homologous recombination is essential for repair of DNA double-strand breaks. Central to this process is a family of recombinases, including archeal RadA and human RAD51, which form nucleoprotein filaments on damaged single-stranded DNA ends and facilitate their ATP-dependent repair. ATP binding and hydrolysis are dependent on the formation of a nucleoprotein filament comprising RadA/RAD51 and single-stranded DNA, with ATP bound between adjacent protomers. We demonstrate that truncated, monomeric Pyrococcus furiosus RadA and monomerised human RAD51 retain the ability to bind ATP and other nucleotides with high affinity. We present crystal structures of both apo and nucleotide-bound forms of monomeric RadA. These structures reveal that while phosphate groups are tightly bound, RadA presents a shallow, poorly defined binding surface for the nitrogenous bases of nucleotides. We suggest that RadA monomers would be constitutively bound to nucleotides in the cell and that the bound nucleotide might play a structural role in filament assembly.

PMID: 27419043 [PubMed]

Categories: Publications
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