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Three ATP-binding cassette (ABC)-superfamily multidrug efflux pumps are known to be responsible for chemoresistance; P-glycoprotein (ABCB1), MRP1 (ABCC1) and ABCG2 (BCRP). These transporters play an important role in normal physiology by protecting tissues from toxic xenobiotics and endogenous metabolites. Hydrophobic amphipathic compounds, including many clinically used drugs, interact with the substrate-binding pocket of these proteins via flexible hydrophobic and H-bonding interactions. These efflux pumps are expressed in many human tumors, where they likely contribute to resistance to chemotherapy treatment. However, the use of efflux-pump modulators in clinical cancer treatment has proved disappointing. Single nucleotide polymorphisms in ABC drug-efflux pumps may play a role in responses to drug therapy and disease susceptibility. The effect of various genotypes and haplotypes on the expression and function of these proteins is not yet clear, and their true impact remains controversial.

Many (dietary) bitter compounds, e.g. flavonoids, activate bitter receptor hTAS2R39 in cell-based assays. Several flavonoids, amongst which some flavanones, are known not to activate this receptor. As certain flavanones are known to mask bitter taste sensorially, flavanones might act as bitter receptor antagonists. Fourteen flavanones were investigated for their potential to reduce activation of hTAS2R39 by epicatechin gallate (ECG), one of the main bitter compounds occurring in green tea. Three flavanones showed inhibitory behavior towards the activation of hTAS2R39 by ECG: 4'-fluoro-6-methoxyflavanone, 6,3'-dimethoxyflavanone, and 6-methoxyflavanone (in order of decreasing potency). The 6-methoxyflavanones also inhibited activation of hTAS2R14 (another bitter receptor activated by ECG), though to a lesser extent. Dose-response curves of ECG at various concentrations of the full antagonist 4'-fluoro-6-methoxyflavanone and wash-out experiments indicated reversible insurmountable antagonism. The same effect was observed for the structurally different agonist denatonium benzoate.

HLA recognition by a killer receptor The interaction between the three-domain killer immunoglobulin receptor (KIR3D) and human leukocyte antigen (HLA) class I molecules is central to the regulation of natural killer cell activity, as well as being key to the control of HIV replication and some haematological malignancies. The crystal structure of a complex between a KIR3D and a self-peptide bearing HLA-B57 molecule has now been determined. The structure shows why the KIR3D family is specific for the HLA-B locus, whereas KIR2D receptors are restricted to HLA-C. Members of the killer cell immunoglobulin-like receptor (KIR) family, a large group of polymorphic receptors expressed on natural killer (NK) cells, recognize particular peptide-laden human leukocyte antigen (pHLA) class I molecules and have a pivotal role in innate immune responses 1 . Allelic variation and extensive polymorphism within the three-domain KIR family (KIR3D, domains D0–D1–D2) affects pHLA binding specificity and is linked to the control of viral replication and the treatment outcome of certain haematological malignancies 1 , 2 , 3 . Here we describe the structure of a human KIR3DL1 receptor bound to HLA-B*5701 complexed with a self-peptide. KIR3DL1 clamped around the carboxy-terminal end of the HLA-B*5701 antigen-binding cleft, resulting in two discontinuous footprints on the pHLA. First, the D0 domain, a distinguishing feature of the KIR3D family, extended towards β2-microglobulin and abutted a region of the HLA molecule with limited polymorphism, thereby acting as an ‘innate HLA sensor’ domain. Second, whereas the D2–HLA-B*5701 interface exhibited a high degree of complementarity, the D1–pHLA-B*5701 contacts were suboptimal and accommodated a degree of sequence variation both within the peptide and the polymorphic region of the HLA molecule. Although the two-domain KIR (KIR2D) and KIR3DL1 docked similarly onto HLA-C 4 , 5 and HLA-B respectively, the corresponding D1-mediated interactions differed markedly, thereby providing insight into the specificity of KIR3DL1 for discrete HLA-A and HLA-B allotypes. Collectively, in association with extensive mutagenesis studies at the KIR3DL1–pHLA-B*5701 interface, we provide a framework for understanding the intricate interplay between peptide variability, KIR3D and HLA polymorphism in determining the specificity requirements of this essential innate interaction that is conserved across primate species.

Ubiquitin-like proteins (UBLs) are conjugated by dynamic E1–E2–E3 enzyme cascades. E1 enzymes activate UBLs by catalysing UBL carboxy-terminal adenylation, forming a covalent E1˜UBL thioester intermediate, and generating a thioester-linked E2˜UBL product, which must be released for subsequent reactions. Here we report the structural analysis of a trapped UBL activation complex for the human NEDD8 pathway, containing NEDD8’s heterodimeric E1 (APPBP1–UBA3), two NEDD8s (one thioester-linked to E1, one noncovalently associated for adenylation), a catalytically inactive E2 (Ubc12), and MgATP. The results suggest that a thioester switch toggles E1–E2 affinities. Two E2 binding sites depend on NEDD8 being thioester-linked to E1. One is unmasked by a striking E1 conformational change. The other comes directly from the thioester-bound NEDD8. After NEDD8 transfer to E2, reversion to an alternate E1 conformation would facilitate release of the E2˜NEDD8 thioester product. Thus, transferring the UBL’s thioester linkage between successive conjugation enzymes can induce conformational changes and alter interaction networks to drive consecutive steps in UBL cascades. The structure of the enzyme E1 bound to its four substrates is described, showing how a thioester switch toggles E1-E2 affinities. Transferring the Ubl's thioester linkage between successive conjugation enzymes induces striking conformational changes and alters interaction networks to drive consecutive steps in Ubl cascades.

Key Points RNA pseudoknots are structural motifs in RNA that are increasingly recognized in viral and cellular RNAs. They have been shown to have a various roles in virus and cellular gene expression. Pseudoknots are formed upon base pairing of a single-stranded region of RNA in the loop of a hairpin to a stretch of complementary nucleotides elsewhere in the RNA chain. This simple folding strategy can generate a large number of stable three-dimensional folds, which display a diverse range of highly specific functions. Pseudoknot function is frequently associated with interactions with ribosomes. The inclusion of pseudoknots in an mRNA can thus confer unusual translational properties. Many RNA viruses use pseudoknots in the control of viral RNA translation, replication and the switch between the two processes. Some satellite viruses encode ribozymes with active sites that are folded by a pseudoknot. In cellular RNAs, pseudoknots are associated with all aspects of mRNA function and also ribosome function, as ribosomal RNAs contain numerous pseudoknots. Other essential cellular pseudoknots have been described in telomerase RNA and transfer messenger RNA. Future research into pseudoknots will focus on structure–function relationships and bioinformatics identification of pseudoknots in genomes. The use of pseudoknots in antiviral applications could also become more widespread. RNA pseudoknots have been identified in many different viral and cellular RNAs and are known to have various roles in virus and cellular gene expression. Here, Ian Brierley and colleagues review viral pseudoknots and the role of these structural motifs in virus gene expression and genome replication. RNA pseudoknots are structural elements found in almost all classes of RNA. First recognized in the genomes of plant viruses, they are now established as a widespread motif with diverse functions in various biological processes. This Review focuses on viral pseudoknots and their role in virus gene expression and genome replication. Although emphasis is placed on those well defined pseudoknots that are involved in unusual mechanisms of viral translational initiation and elongation, the broader roles of pseudoknots are also discussed, including comparisons with relevant cellular counterparts. The relationship between RNA pseudoknot structure and function is also addressed.

Within the flavonoid class of natural products the prenylated sub-class is quite rich in structural variety and pharmacological activity. In the last twenty years a huge number of new structures has been reported, mostly from Leguminosae and Moraceae, with few coming from other genera. The presence, in different forms, of the isoprenoid chain can lead to impressive changes in biological activity, mostly attributed to an increased affinity for biological membranes and to an improved interaction with proteins. Molecules, such as xanthohumol and sophoraflavanone G, while being very structurally simple, show numerous pharmacological applications and are ideal candidates for SAR aimed to the discovery of new drugs. Only recently the biogenesis of these compounds has been more extensively studied and much attention has been focused on the enzymes involved in the modification and transfer of the prenyl unit.

Podophyllotoxin is an antimitotic natural product. Its inhibitory activity on cell growth led to the development of the clinically valuable anticancer agents, etoposide, teniposide and the water-soluble prodrug, etoposide phosphate. The cytotoxic mechanism of these drugs is the inhibition of topoisomerase II, unlike the lead compound which inhibits mitosis. Through extensive structure-activity relationship studies, several potential drug candidates were synthesized such as GL-331, TOP 53, NK611, and azatoxin. Recently, more complex and diverse analogues have been synthesized either to get more potent compounds or to overcome drug resistance. At the same time, a number of prodrug approaches have been tried to enhance the tumor selectivity or to increase the aqueous solubility. The prodrugs can release cytotoxic etoposide through the actions of hydrolysis, enzymes or catalytic antibodies. More sophisticated prodrug strategies have been applied in etoposide and these produced some interesting results. In this review, the current research trends in the design of new derivatives will be covered with a brief introduction of podophyllotoxin and related analogues.