The structure-based design of Mdm2/Mdmx-p53 inhibitors gets serious

The p53 protein is the cell's principal bastion of defense against tumor-associated DNA damage. Commonly referred as a "guardian of the genome", p53 is responsible for determining the fate of the cell when the integrity of its genome is damaged. The development of tumors requires breaching this defense line. All known tumor cells either mutate the p53 gene, or in a similar number of cases, use internal cell p53 modulators, Mdm2 and Mdmx proteins, to disable its function. The release of functional p53 from the inhibition by Mdm2 and Mdmx should in principle provide an efficient, nongenotoxic means of cancer therapy. In recent years substantial progress has been made in developing novel p53-activating molecules thanks to several reported crystal structures of Mdm2/x in complex with p53-mimicking peptides and nonpeptidic drug candidates. Understanding the structural attributes of ligand binding holds the key to developing novel, highly effective, and selective drug candidates. Two low-molecular-weight compounds have just recently progressed into early clinical studies.     

The Painleve Ping-Pong P IV

We construct a transformation which generates new solutions for a one-parameter family of the fourth Painlevé equations. We obtain solutions with the same parameter values as in the given equation. Also we obtain new relations between two Painlevé transcendents of the fourth kind with different free parameters.     

The gauge field copies through the Bäcklund transformation for the Liouville equation

It is shown that the gauge field copies for the field strength tensor associated with the Lax pair of the Liouville equation are generated through the non-auto Bäcklund transformations.     

Structure of the stapled p53 peptide bound to Mdm2

Mdm2 is a major negative regulator of the tumor suppressor p53 protein, a protein that plays a crucial role in maintaining genome integrity. Inactivation of p53 is the most prevalent defect in human cancers. Inhibitors of the Mdm2-p53 interaction that restore the functional p53 constitute potential nongenotoxic anticancer agents with a novel mode of action. We present here a 2.0 ? resolution structure of the Mdm2 protein with a bound stapled p53 peptide. Such peptides, which are conformationally and proteolytically stabilized with all-hydrocarbon staples, are an emerging class of biologics that are capable of disrupting protein-protein interactions and thus have broad therapeutic potential. The structure represents the first crystal structure of an i, i + 7 stapled peptide bound to its target and reveals that rather than acting solely as a passive conformational brace, a staple can intimately interact with the surface of a protein and augment the binding interface.     

Bäcklund transformation,local and non-local conservation laws for super-chiral fields

New non-local conservation laws, parametric Bäcklund transformation and local conservation laws are constructed for super-chiral fields in general, using similar methods for ordinary chiral fields. We thus have a unified view of these field theories.     

Representations of the CAR generated by the representations of the CCR III. non-Fock extension

An idea to construct a representation of the CAR algebra in a representation of the CCR algebra, which succeeded in the Fock case, is verified for the simplest non-Fock extensions of the formalism.     

The Photocatalyzed Thiol-ene reaction: A New Tag to Yield Fast,Selective and reversible Paramagnetic Tagging of Proteins

Paramagnetic restraints have been used in biomolecular NMR for the last three decades to elucidate and refine biomolecular structures, but also to characterize protein-ligand interactions. A common technique to generate such restraints in proteins, which do not naturally contain a (paramagnetic) metal, consists in the attachment to the protein of a lanthanide-binding-tag (LBT). In order to design such LBTs, it is important to consider the efficiency and stability of the conjugation, the geometry of the complex (conformational exchanges and coordination) and the chemical inertness of the ligand. Here we describe a photo-catalyzed thiol-ene reaction for the cysteine-selective paramagnetic tagging of proteins. As a model, we designed an LBT with a vinyl-pyridine moiety which was used to attach our tag to the protein GB1 in fast and irreversible fashion. Our tag T1 yields magnetic susceptibility tensors of significant size with different lanthanides and has been characterized using NMR and relaxometry measurements.