Protein-protein docking: is the glass half-full or half-empty?

Are current docking methods capable of building complexes from putative component protein structures? Results of recent computational studies, including those of the CAPRI (Critical Assessment of Protein Interactions) competition, were used to determine the key properties for successful docking and introduce a classification of protein complexes based on docking difficulty. Enzyme-inhibitor complexes could be determined with reasonable accuracy - possibly to within a few alternative structures. Results for antigen-antibody pairs are less predictable, and data for small signaling complexes are generally poor. However, moderate amounts of experimental data can remove uncertainty and the methodology is rapidly improving. Transient complexes with large interface areas undergo substantial conformational change and are beyond the reach of current docking methods. The docking of such complexes might therefore require fundamentally new approaches.     

The avian immune genome--a glass half-full or half-empty?

Although in broad terms the avian immune response is remarkably similar to that of mammals, when one looks at specifics birds have a different repertoire of immune organs, cells and molecules compared to those characterized in mammals. Birds lack organized lymph nodes, yet have the Bursa of Fabricius. Birds lack neutrophils and functional eosinophils, yet have a distinct group of polymorphonuclear granulocytes known as heterophils. Birds also have a different repertoire of cytokines, chemokines, Toll-like receptors, defensins and integrins, as detailed in this review.     

Marijuana-based drugs: innovative therapeutics or designer drugs of abuse?

The principal psychoactive component of marijuana, Δ(9)-tetrahydrocannabinol (THC), activates CB1 cannabinoid receptors (CB1Rs). Unfortunately, pharmacological research into the design of effective THC analogs has been hampered by psychiatric side effects. THC-based drug design of a less academic nature, however, has led to the marketing of "synthetic marijuana," labeled as K2 or "Spice," among other terms, which elicits psychotropic actions via CB1R activation. Because of structural dissimilarity to THC, the active ingredients of K2/Spice preparations are widely unregulated. The K2/Spice "phenomenon" provides a context for considering whether marijuana-based drugs will truly provide innovative therapeutics or merely perpetuate drug abuse.     

Antimalarial drugs: is the lysosomotropic hypothesis still valid?

Although quinine and its congener chloroquine have been used as antimalarials for many years, and their analog, mefloquine, has been recently introduced, the precise mode of action of these quinoline-containing drugs is not fully understood. The lysosomotropic hypothesis is favoured and Hagai Ginsburg here discusses its principles and its reliability in view of both the physicochemical character of the drugs and new experimental evidence.     

Implications of cnidarian gene expression patterns for the origins of bilaterality is the glass half full or half empty?

The past two years have seen a dramatic increase in the availabledata on gene sequence and gene expression for cnidarians andother "lower" Metazoa, and a flurry of recent papers has drawnon these to address the origins of bilaterality. Cnidarian homologsof many genes that play key roles in the specification of boththe A/P and D/V axes of bilaterians have been characterized,and their patterns of expression determined. Some of these expressionpatterns are consistent with the possibility of conservationof function between Cnidaria and Bilateria, but others clearlydiffer. Moreover, in some cases very different interpretationshave been made on the basis of the same, or similar, data. Inpart, these differences reflect the inevitable uncertaintiesassociated with the depth of the divergence between cnidariansand bilaterians. In this article, we briefly summarize the cnidariandata on gene expression and organization relevant to axis formation,the varying interpretations of these data, and where they conflict.Our conclusion is that the presently available data do not allowus to unequivocally homologize the single overt axis of cnidarianswith either of the bilaterian axes.     

Locomotor impairment of gravid lizards: is the burden physical or physiological?

Pregnancy is associated with reduced locomotor performance in several reptile species, but the reasons for this reduction remain unclear. Previous authors generally have assumed that the decreased maternal mobility is due to the physical burden of the clutch, but our data on a viviparous Tasmanian scincid lizard (Niveoscincus microlepidotum) suggest a different interpretation. Running speeds of gravid female skinks decrease during gestation (as litter mass increases), but this locomotor impairment is due to physiological changes associated with pregnancy, rather than simple physical burdening. Maternal running speeds are unrelated to litter masses, and do not increase in the week after parturition. Females with very large abdominal fat‐bodies (due to ad libitum feeding in the laboratory), equivalent in mass to the litter, nonetheless run rapidly. If the locomotor ‘costs’ of reproduction reflect all‐or‐none physiological changes associated with pregnancy, then the magnitude of such costs may correlate only weakly with the actual level of reproductive investment. Because life‐history models predict that the relationship between fecundity and ‘cost’ has important evolutionary consequences, our results highlight the need to clarify the causal basis for locomotor impairment in gravid reptiles.     

Crested Saguaros: What is the Rhyme or Reason?

Plant Molecular Biology Reporter -     

Sulfur signaling: is the agent sulfide or sulfane?

Triplex-forming oligonucleotides (TFOs) are sequence-dependent DNA binders that may be useful for DNA targeting and detection. A sensitive and convenient method to monitor triplex formation by a TFO and its target DNA duplex is required for the application of TFO probes. Here we describe a novel design by which triplex formation can be monitored homogeneously without prelabeling the target duplex. The design uses a TFO probe tagged with a fluorophore that undergoes fluorescence resonance energy transfer with fluorescent dyes that intercalate into the target duplex. Through color compensation analysis, the specific emission of the TFO probe reveals the status of the triple helices. We used this method to show that triple helix formation with TFOs is magnesium dependent. We also demonstrated that the TFO probe can be used for detection of sequence variation in melting analysis and for DNA quantitation in real-time polymerase chain reaction.     

Valency or wählency: is the epitope diversity of the B-cell response regulated or chemically determined?

For almost a century, the humoral immune response has been monitored principally by the measurement of antibody concentrations, although antibody affinity and isotype have also long been acknowledged as critical to their biological activity. In this report, it is argued that these measures alone may provide a poor measure of the activity of serum antibodies. A B-cell response that is directed against multiple epitopes on a protein can form immune complexes bearing multiple antibody molecules. This is essential for the efficient initiation of processes such as the complement cascade and the activation of leucocytes via Fc receptors. These processes can be dramatically enhanced when B cells target a greater number of epitopes on any antigen. Evidence that the epitope diversity of an immune response may vary between individuals, and that it may vary in an individual over time, is reviewed. This variability is likely to be influenced by a number of host-specific factors in addition to antigen chemistry. The appropriateness of the chemically deterministic term 'antigen valency' to describe the number of epitopes recognized by an individual's B-cell response is discussed, and the term 'w?hlency' to emphasize the situational nature of B-cell epitopes is introduced.     

TonB or not TonB: is that the question?

Bacteria are able to survive in low-iron environments by sequestering this metal ion from iron-containing proteins and other biomolecules such as transferrin, lactoferrin, heme, hemoglobin, or other heme-containing proteins. In addition, many bacteria secrete specific low molecular weight iron chelators termed siderophores. These iron sources are transported into the Gram-negative bacterial cell through an outer membrane receptor, a periplasmic binding protein (PBP), and an inner membrane ATP-binding cassette (ABC) transporter. In different strains the outer membrane receptors can bind and transport ferric siderophores, heme, or Fe3+ as well as vitamin B12, nickel complexes, and carbohydrates. The energy that is required for the active transport of these substrates through the outer membrane receptor is provided by the TonB/ExbB/ExbD complex, which is located in the cytoplasmic membrane. In this minireview, we will briefly examine the three-dimensional structure of TonB and the current models for the mechanism of TonB-dependent energy transduction. Additionally, the role of TonB in colicin transport will be discussed.     

Stochastic or deterministic: what is the effective population size of HIV-1?

Various studies have attempted to estimate the effective population size of HIV-1 to determine the strength of stochastic effects in within-host evolution. The largely discrepant estimates, the complexity of the concept of the effective population size and the resulting uncertainty about the underlying assumptions make the interpretation of these estimates difficult. Here, we explain the concept and critically assess the current estimates. We discuss the biologically relevant factors that affect the estimate and use of the effective population size. We argue that these factors lead to an underestimation of the effective population size and, thus, to an overestimation of the strength of stochastic effects in HIV-1 evolution.