Volume 6 Issue 8, August 2010

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.

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.

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.

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.

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.

Amide bonds are routinely formed in biological systems using carboxylic acids that have been activated at the expense of ATP. The biochemical characterization of a putative β-lactamase now reveals a new way to form amide bonds using stable methyl ester intermediates.

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.

MCL-1 has emerged as a major oncogenic and chemoresistance factor. A screen of stapled peptide helices identified the MCL-1 BH3 domain as selectively inhibiting MCL-1 among the related anti-apoptotic Bcl-2 family members, providing insights into the molecular determinants of binding specificity and a new approach for sensitizing cancer cells to apoptosis.

The lipocalin protein Scn-Ngal is known to bind iron-chelating siderophores, leading to inhibition of bacterial growth. New results reveal that Scn-Ngal, in the absence of bacterial infection, can form a complex with catechol that binds and transports iron in vivo.

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.

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.

Small RNAs targeted to gene promoters are known regulators of transcription in mammalian cells. Antigene RNAs complementary to non-coding transcripts localized to the 3′ termini of genes are now shown to regulate transcription across long genomic sequences.