An evolutionary bridge to a new protein fold

Arc repressor bearing the N11L substitution (Arc-N11L) is an evolutionary intermediate between the wild type protein, in which the region surrounding position 11 forms a beta-sheet, and a double mutant 'switch Arc', in which this region is helical. Here, Arc-N11L is shown to be able to adopt either the wild type or mutant conformations. Exchange between these structures occurs on the millisecond time scale in a dynamic equilibrium in which the relative populations of each fold depend on temperature, solvent conditions and ligand binding. The N11L mutation serves as an evolutionary bridge from the beta-sheet to the helical fold because in the mutant, Leu is an integral part of the hydrophobic core of the new structure but can also occupy a surface position in the wild type structure. Conversely, the polar Asn 11 side chain serves as a negative design element in wild type Arc because it cannot be incorporated into the core of the mutant fold.     

A Ku bridge over broken DNA

The Ku heterodimer is essential for the nonhomologous end-joining pathway of DNA double-strand break repair; it both protects the broken ends and recruits some of the many proteins required to complete repair. The recently determined structure of Ku provides insights into how it can both bind to the DNA ends and allow access by the other proteins required to rejoin them.     

A bridge between chemistry and biology

Chemical biology is an interdisciplinary field that is undergoing rapid expansion around the globe. Recently, the Japanese Society for Chemical Biology sponsored its inaugural scientific meeting to discuss research at the interface of chemistry and biology.     

A concerted mechanism for berberine bridge enzyme

Berberine bridge enzyme catalyzes the conversion of (S)-reticuline to (S)-scoulerine by formation of a carbon-carbon bond between the N-methyl group and the phenolic ring. We elucidated the structure of berberine bridge enzyme from Eschscholzia californica and determined the kinetic rates for three active site protein variants. Here we propose a catalytic mechanism combining base-catalyzed proton abstraction with concerted carbon-carbon coupling accompanied by hydride transfer from the N-methyl group to the N5 atom of the FAD cofactor.     

A YY1 bridge for X inactivation

A landmark genomics project is taking shape in Africa that shifts the power and prominence to local scientists. If successful, the program will offer valuable insights into the inheritance of common diseases and reshape the paradigm of foreign-funded research.     

New naphthylcombretastatins. Modifications on the ethylene bridge

Compounds with three aromatic systems, carrying a 2-naphthalene and a 3,4,5-trimethoxyphenyl moieties bonded to five-membered, six-membered or fused heterocycles display potent cytotoxic effect and inhibition of tubulin polymerization, in agreement with their structural similarity to combretastatins and their heterocyclic analogues.     

Methylene versus carbonyl bridge in the structure of new tubulin polymerization inhibitors with tricyclic A-rings

The phenothiazine group has been identified as a suitable A ring in the structure of tubulin polymerization inhibitors. In our search to identify more potent inhibitors, a study of different isosteric tricyclic groups as new potential A rings was first realized and permitted to identify 1-azaphenothiazine and iminodibenzyl as favorable modulations providing compounds with improved activity against tubulin. An investigation of the methylene group as the connector between the A and B rings revealed that the “CH₂” bridge was tolerated, improving the biological potency when the A unit was of phenothiazine, 1-azaphenothiazine or iminodibenzyl type. Molecules 6–8 and 12 showed increased biological activity in comparison to parent phenstatin 2 on COLO 205 colon cancer cell line. The most antineoplastic agent in the current study was phenothiazine 5 displaying a GI₅₀ of 25 nM against the melanoma MDA-MB-435 cell line.