Molecular basis of the activity of the phytopathogen pectin methylesterase.

We provide a mechanism for the activity of pectin methylesterase (PME), the enzyme that catalyses the essential first step in bacterial invasion of plant tissues. The complexes formed in the crystal using specifically methylated pectins, together with kinetic measurements of directed mutants, provide clear insights at atomic resolution into the specificity and the processive action of the Erwinia chrysanthemi enzyme. Product complexes provide additional snapshots along the reaction coordinate. We previously revealed that PME is a novel aspartic-esterase possessing parallel β-helix architecture and now show that the two conserved aspartates are the nucleophile and general acid-base in the mechanism, respectively. Other conserved residues at the catalytic centre are shown to be essential for substrate binding or transition state stabilisation. The preferential binding of methylated sugar residues upstream of the catalytic site, and demethylated residues downstream, drives the enzyme along the pectin molecule and accounts for the sequential pattern of demethylation produced by both bacterial and plant PMEs

Hsp90 chaperone in disease

The molecular chaperone Hsp90 is at the heart of protein homeostasis control. A wide range of pathologies disturbs protein homeostasis, thus placing Hsp90 at the crossroads of many diseases. Here, we evaluate the impact of recent progress in understanding the molecular mechanism of Hsp90-client interactions and their role in disease. We discuss the role of Hsp90 for hormonal imbalances, cancer and neurodegenerative disorders. For each disease class we discuss implications of complexes in which Hsp90 binds to a paradigmatic client: the transcription factor Glucocorticoid Receptor, the kinase Cdk4 and the microtubule stabilizer Tau. The mechanistic insights allow us to elaborate on possible therapeutic intervention routes. Hsp90 is a druggable chaperone. Thus, understanding Hsp90 biology at molecular resolution offers an interesting approach to tackle protein-related diseases