Articles in 2010

Although FPPS is a potential anti-cancer target, the high bone affinity of nitrogen-containing bisphosphonates, FPPS inhibitors used clinically to treat bone disease, has prevented their development as cancer therapeutics. Using fragment-based drug discovery, non-bisphosphonate inhibitors were discovered that bind in a previously undescribed allosteric pocket.

A chemical array screen identifies a small-molecule inhibitor of pirin that inhibits its interaction with the oncoprotein Bcl3 and decreases the expression of the tumor mobility protein SNAI2. As a result, the compound perturbs the migration of melanoma cells that have high pirin expression levels.

Biotin synthesis is known to include a pimelate intermediate, the construction of which is controversial. Genetic manipulations and chemical feeding now demonstrate that the two mystery enzymes in the process create and cleave a methyl ester that sends a biotin precursor into the fatty acid synthesis machinery.

Probing the biological location and function of transition metals has proven difficult. X-ray fluorescence microscopy in combination with an array of metal chelators now provides a way to interrogate zinc in maturing mouse oocytes, demonstrating a role for this metal in cell division.

Selectivity is a key obstacle in drug development. A new study describes how “peptide stapling,” a technique for making peptide α-helices more potent and cell permeable, allows the design of MCL-1 inhibitors with extraordinary selectivity.

Siderocalin (also known as lipocalin 2) is a component of the innate immune system that binds and sequesters bacterial iron compounds in the blood and urine. A new study identifies iron–catechol complexes as endogenous ligands for siderocalin, which can deliver the iron compounds to the kidney.

Time-resolved fluorescence resonance energy transfer (TR-FRET) measurements with selective, fluorescently labeled ligands support the existence of GPCR dimers in native tissues and suggest that activated GPCR dimers are asymmetric.

Protein structures are considerably stabilized by local interactions. A new computational and structural analysis discovers that n→π^* interactions between consecutive residues are stabilizing and ubiquitous in a variety of secondary structures.

The expanding biotechnology landscape offers new intersections with traditional strengths in chemical biology.

Excitatory synapses are located in confined chemical spaces called the dendritic spines. These are atypical femtoliter-order microdomains where the behavior of even single molecules may have important biological consequences. Powerful chemical biological techniques have now been developed to decipher the dynamic stability of the synapses and to further interrogate the complex properties of neuronal circuits.

A variety of natural C-nitroso compounds are known, but the path to these important functional groups has been a mystery. Elucidation of the biosynthetic route to an iron chelator now reveals a tyrosinase-like copper-containing monooxygenase as responsible for the transformation.

Instability of (CTG)•(CAG) repeats in microsatellite DNA has been linked to numerous neurological diseases. Probing trinucleotide repeat structures using engineered zinc-finger nucleases provides evidence that DNA hairpins form in vivo and are linked to replication-dependent genomic instability.

Current methods to investigate glycosylation allow the identification of modification sites but provide limited additional information. A new strategy using polymers to label specific sugars now shows a huge variety in the occupancy of known glycosylation sites as well as unexpected interplay between post-translational modifications.

TAP is an ABC transporter that contributes to antigen presentation by transporting peptides from the cytosol to the ER lumen for loading onto MHC-I. Viral evaders of the host immune system take advantage of TAP’s structure as well as its ATP-binding ability and have provided new insight into its function.

Proteins rely on a combination of intramolecular forces to form and stabilize their structures. A careful comparison of computational analysis and high-resolution crystal structures now indicates that the n→π* interaction merits inclusion in this group.

Evidence for the existence and importance of GPCR dimers and oligomers is mounting, but direct detection of these species has been challenging. The development of improved fluorescent ligands for time-resolved spectroscopy confirms their presence across GPCR families and in native tissue.

Proteomic analysis in dendritic cells identifies three palmitoylation sites within IFITM3, an innate immunity protein involved in inhibition of early replication of several viruses. Palmitoylation of IFITM3 regulates its clustering in membranes and is crucial for inhibition of influenza virus infection.