Max-Planck-Gesellschaft Zur F&#xf6;rderung Der Wissenschaften E. V.

Alfred Wittinghofer

Herbert Waldmann

Pablo Antonio Martin-Gago

Christian Jelich-Ottmann

Philippe Bastiaens

Claudia Oecking

Christian Klein

Eyad Kalawy Fansa

Sandip Murarka

Martin Würtele

Pablo Antonio MARTÍN-Gago

The present invention relates to novel substituted benzene disulfonamides, as well as pharmaceutical compositions containing at least one of these substituted benzene disulfonamides together with at least one pharmaceutically acceptable carrier, excipient and/or diluent. Said substituted benzene disulfonamides are binding to the prenyl binding pocket of PDE6&#x3b4; and therefore, are useful for the prophylaxis and treatment of cancer by inhibition of the binding of PDE6&#x3b4; to farnesylated Ras proteins and thereby, inhibition of oncogenic Ras signaling in cells.

Benzene disulfonamide for the treatment of cancer

The present invention relates to a crystal of a ternary complex composed of the protein 14-3-3, a ligand thereof and a fragment of Plasma Membrane ATPase (PMA) comprising the coordinates of table 4 or coordinates which differ from the coordinates of table 4 by a root mean square deviation of the C-alpha atoms of less than 3 Angstrom, wherein (a) protein 14-3-3 consists of the amino acid sequence of SEQ ID NO: 1 or of the sequence of a species homolog; (b) the ligand is Fusicocdin; (c) PMA is a C-terminal peptide of up to 15 amino acid residues in length; comprising the amino acid sequence of SEQ ID NO: 2 or comprising the sequence of a species homolog. Moreover, the invention also relates to methods for obtaining crystals of 14-3-3 in ternary complex and to methods relating to the determination of said 14-3-3 crystal coordinates. In addition, the present invention relates to computer modeling of crystal coordinates, to methods for developing a ligand binding to the complex of protein 14-3-3 and PMA and to methods for identifying a potential ligand to the complex of 14-3-3 and PMA. Furthermore, the present invention relates to a method for identifying and selecting a protein or protein complex with increased affinity to a ligand, to nucleic acid molecules encoding PMA or 14-3-3 with decreased affinity to a ligand and to methods of generating transgenic plants encoding PMA or 14-3-3 with decreased affinity to said ligand. Finally, the present invention relates to a device for developing a ligand for the complex of PMA and 14-3-3 and to the use of said device.

Crystal structure of the ternary complex of 14-3-3/Fusicoccin/PMA and methods for designing new herbicides

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Herdecke, Germany

Alfred Wittinghofer