A Designed Enzyme Promotes Selective Post‐translational Acylation

A computationally designed, allosterically regulated catalyst (CaM M144H) produced by substituting a single residue in calmodulin, a non‐enzymatic protein, is capable of efficient and site selective post‐translational acylation of lysines in peptides with highly diverse sequences. Calmodulin′s binding partners are involved in regulating a large number of cellular processes; this new chemical‐biology tool will help to identify them and provide structural insight into their interactions with calmodulin.     

Phase growth competition in solid/liquid reactions between copper or Cu3Sn compound and liquid tin-based solder

Interfacial reaction between solid ?-Cu₃Sn compound and liquid Sn at 250 °C is studied for the first time. The reaction product formed at the ?-Cu₃Sn/liquid Sn interface consists of the single η-Cu₆Sn₅ phase. The growth kinetics of the η phase formed at the incremental ?/liquid Sn couple (?/η/Sn configuration) is compared to that of η phase formed at the classical Cu/liquid Sn couple (Cu/?/η/Sn configuration). The experimental method consists first in processing of intimate interfaces by dipping peaces of solid ?-Cu₃Sn compound and Cu in liquid Sn for 1 s at 250 °C. Afterwards, isothermal holding of such pre-performed couples for 10, 30, 120 and 480 min at 250 °C are performed for both couples. A theoretical analysis of the growth kinetics of η phase and comparison of its growth in both configurations are performed.     

Topological network alignment uncovers biological function and phylogeny

Sequence comparison and alignment has had an enormous impact on our understanding of evolution, biology and disease. Comparison and alignment of biological networks will probably have a similar impact. Existing network alignments use information external to the networks, such as sequence, because no good algorithm for purely topological alignment has yet been devised. In this paper, we present a novel algorithm based solely on network topology, that can be used to align any two networks. We apply it to biological networks to produce by far the most complete topological alignments of biological networks to date. We demonstrate that both species phylogeny and detailed biological function of individual proteins can be extracted from our alignments. Topology-based alignments have the potential to provide a completely new, independent source of phylogenetic information. Our alignment of the protein–protein interaction networks of two very different species—yeast and human—indicate that even distant species share a surprising amount of network topology, suggesting broad similarities in internal cellular wiring across all life on Earth.     

Identification of HDAC6‐Selective Inhibitors of Low Cancer Cell Cytotoxicity

The histone deacetylases (HDACs) occur in 11 different isoforms, and these enzymes regulate the activity of a large number of proteins involved in cancer initiation and progression. The discovery of isoform‐selective HDAC inhibitors (HDACIs) is desirable, as it is likely that such compounds would avoid some of the undesirable side effects found with the first‐generation inhibitors. A series of HDACIs previously reported by us were found to display some selectivity for HDAC6 and to induce cell‐cycle arrest and apoptosis in pancreatic cancer cells. In the present work, we show that structural modification of these isoxazole‐based inhibitors leads to high potency and selectivity for HDAC6 over HDAC1–3 and HDAC10, while unexpectedly abolishing their ability to block cell growth. Three inhibitors with lower HDAC6 selectivity inhibit the growth of cell lines BxPC3 and L3.6pl, and they only induce apoptosis in L3.6pl cells. We conclude that HDAC6 inhibition alone is insufficient for disruption of cell growth, and that some degree of class 1 HDAC inhibition is required. Moreover, the highly selective HDAC6Is reported herein that are weakly cytotoxic may find use in cancer immune system reactivation.