Volume 7 Issue 10, October 2011

Centrioles are among the most beautiful of biological structures. How their highly conserved nine-fold symmetry is generated is a question that has intrigued cell biologists for decades. Two recent structural studies provide the tantalizing suggestion that the self-organizing properties of the SAS-6 protein hold the answer.

The extent to which ligand-free GPCRs exist in quasi-stable 'precoupled' complexes with G proteins in vivo is uncertain. New research, using fluorescence recovery after photobleaching (FRAP), reveals a structural requirement for and functional consequences of muscarinic acetylcholine receptor–G_q protein preassembly.

The glycosyltransferase-catalyzed generation of sugar nucleotides is normally an unfavorable endothermic process. Simple reactive glycosides used in conjunction with mutant transferases enable such reactions to become favorable exothermic processes, providing practical access to a diverse range of non-natural sugar nucleotides.

Purine riboswitches have served as models for riboswitch structure, dynamics, evolution and engineering. New crystallographic models reveal the adaptability of a purine riboswitch evolved to bind 2′-deoxyguanosine and highlight challenges inherent to riboswitch engineering.

Monitoring oxygen (O₂) levels is essential to optimizing aerobic metabolism and ensuring proper biological processes in most eukaryotes. The spice chemosensor TRPA1 is a previously unidentified O₂ sensor in the mammalian sensory nervous system that warns against hyperoxia and hypoxia.

A combination of chemical and genetic approaches has established a proof of concept in mouse models—with strong mechanistic underpinning—indicating that targeting the aberrantly recruited histone methyltransferase activity of DOT1L has therapeutic potential in aggressive leukemias driven by MLL fusion genes.

A recent flurry of activity has defined the protein FLOWERING LOCUS T (FT) as a mobile signal or 'florigen' that induces flowering. A new study has shown that a 14-3-3 protein links FT to a transcription factor at the plant apex to initiate flowering.

PoxA is a lysyl-tRNA synthetase paralog that post-translationally modifies elongation factor P (EF-P) with a lysine moiety. Further biochemical analysis reveals that (R)-β-lysine, rather than the more abundant α-amino acid, is the preferred substrate for PoxA.

The ribosomal incorporation of a new, more flexible photocrosslinking amino acid allows the identification of client proteins for a chaperone that works during acid stress as well as the discovery of a chaperone-cooperation mechanism that enhances protein refolding upon pH neutralization.

The first high-resolution structures of transaldolase with bound intermediates both define active site residues that necessitate a revision of the current reaction pathway and point to a high-energy intermediate structure and protein conformational changes as mechanisms to promote product formation.

A systematic analysis of possible substrates for reverse glycosyltransferase reactions reveals thermodynamically favored pathways to the traditional 'activated' sugar donors, enabling high-yielding enzymatically coupled sugar transfers and a general colorimetric assay for sugar nucleotide formation and utilization.

A quantitative covalent labeling strategy reveals that multiple ligand-specific conformational states are present in the G protein–coupled β₂-adrenergic receptor. Their existence may underlie 'biased agonism', which describes the differential abilities of agonists to activate distinct signaling mechanisms downstream of GPCRs.

The redox-sensitive TRP channel TRPA1 is activated in hyperoxic and hypoxic conditions directly through modification of cysteine residues by O₂ and indirectly through prolyl hydroxylation by PHDs, enzymes related to the hypoxia-inducible factor HIF-1, thus helping to explain how O₂ is sensed by sensory and vagal neurons.

A screen for compounds that alleviate the inhibitory effect of influenza NS1 on host gene expression and suppress viral toxicity found naphthalimides that could upregulate REDD1, an mTORC1 inhibitor, revealing that viruses inhibit REDD1 to activate the mTORC1 pathway.

A transposon-generated mutation strategy used to find targets of eight antibacterial compounds and compound combinations in Staphylococcus aureus identifies known targets as well as new mechanisms of resistance.

The aromatic compound rifamycin SV binds to expanded and partially compact assembly intermediates and inhibits amyloid fibril formation of β₂-microglobulin by diverting assembly toward soluble, toxic spherical aggregates lacking the classical structure of amyloid.

Monitoring preassembly of the G protein–coupled receptor M3 muscarinic acetylcholine receptor M3R–G_q heterotrimers by FRAP reveals that agonist- and antagonist-insensitive preassembly of inactive-state complexes via a polybasic motif in M3R increases the sensitivity and accelerates the onset of GPCR signaling.

Purine base binding specificity in adenine and guanine riboswitches is governed primarily by specific base pairing interactions in the ligand-binding site. A series of 2′-deoxyguanosine riboswitch structures reveals remodeling of the ligand-binding site and remote regions of the structure to accommodate the sugar moiety of the nucleoside substrate.