Reviews & Analysis

The nonreceptor tyrosine kinase Btk has emerged as a new molecular target for the treatment of B cell lymphoma and autoimmune disorders. A newly discovered specific small-molecule Btk inhibitor that uniquely stabilizes Btk in an inactive conformation suppresses inflammation in rheumatoid arthritis.

Structures of 'on' and 'off' states of Crk reveal how prolyl cis-trans isomerization functions as a molecular switch in this key adaptor protein. Additionally, these structures show how an SH3 domain utilizes a noncanonical binding surface for self-regulation.

To find out which metabolites bind to which proteins, one does not need to start with a hypothesis: it is now easiest just to do the experiments. As it turns out, some metabolites are quite promiscuous, at least in yeast.

Autophagy has emerged as a drug target for various diseases including cancer and neurodegeneration. Small molecules that affect components of the autophagic machinery and signaling pathways have led to new insights into autophagic mechanisms and also serve as lead compounds for therapeutic application.

Conjugation of a known, mechanism-based glycosidase inhibitor to sensitive fluorophores yielded unexpectedly potent and selective probes for quantifying active lysosomal glucocerebrosidase. These conjugates could prove to be invaluable tools for diagnosing and studying Gaucher disease.

Although members of the Hsp70-DnaK family of heat shock proteins are involved in nearly all aspects of cell physiology, some mechanistic details of their mode of action remain obscure. A new substrate helps establish DnaK as an unfoldase that requires as little as five ATP molecules to drive the refolding of one protein.

The glucose-based polymer cellulose is of great biological and economical importance; however, little is known about how cellulose is synthesized. Now, structural estimates of one of the cellulose-synthesizing subunits in the bacterium Acetobacter xylinum help to explain the extrusion of the newly synthesized glucan chains.

A new method to monitor interactions between cell surface proteins reveals that interaction of the neuronal cell surface adhesion proteins neurexin and neuroligin is increased at synapses during a stimulus or developmental activity. This increased activity-dependent surface density of neurexin–neuroligin complexes is subsequently required for maturation of synapses.

Ten significantly active new (R)-transaminases, still very rare enzymes, were found among 21 designed variants obtained from nothing more than existing transaminase structures and alignment of pertinent fingerprints of annotated sequences.

Aminoacylation of tRNA is the cellular process for providing aminoacyl donors for the ribosome synthesis of polypeptides. New research highlights an unexpected structural overlap between enzymes involved in this process and those involved in the biosynthesis of cyclodipeptides, an important class of bioactive molecules.

ATP synthase synthesizes and hydrolyzes ATP by a unique rotational mechanism. A new study elucidates an important step of the catalytic mechanism, the timing of the release of the reaction product P_i in ATP hydrolysis.

Iron-sulfur (Fe-S) clusters are among nature's simplest and most versatile agents of electron transfer. Remarkably, their biological assembly involves an obligatory electron transfer event. It is now revealed that parallel but distinct electron transfer pathways are separately required for compartment-specific Fe-S protein maturation.

Spider dragline silk is an incredibly tough elastomer, but it is also very elastic. Recent work has demonstrated how the mechanical properties of spider silk and other natural elastomers can be mimicked to produce artificial protein-based fibers with great potential for industrial applications.

Mutually exclusive post-translational modifications of flap endonuclease 1 (FEN1) regulate its binding to proliferating cell nuclear antigen (PCNA) and govern its various modes of DNA interaction during DNA replication and repair.

Many natural products are decorated with oxygenated nitrogens, but enzymes capable of forming a stable nitroso species have been elusive. A new study reports the identification of a copper-containing C-nitrososynthase that tightly controls the oxidation state of an aromatic amine to yield the natural product 4-hydroxy-3-nitrosobenzamide.

Manipulation of stem cells is an important therapeutic goal that has proven difficult to achieve. A recent report describes a novel in vivo small-molecule screen and identifies a modulator of mammalian neurogenesis that partially reverses age-related declines in cognition.

Many nuclear and cytoplasmic proteins are post-translationally modified by both O-GlcNAc and phosphate, but determining whether a single copy of a protein bears multiple modifications remains a challenge. A new analytic approach reveals a surprising correlation between phosphorylation and the O-GlcNAc modification.