The dynamics of cyclin dependent kinase structure

In the past year, several new crystal structures have provided exciting insights into the conformational changes underlying the regulation of cyclin-dependent kinases. We now understand the structural basis of many of the mechanisms by which cyclin-dependent kinases are regulated, including activation by cycling binding and phosphorylation, inhibition by the inhibitor p27, and binding by the CKS proteins.     

Toward the development of DNA vaccines

DNA vaccination has proved to be a generally applicable technology in various preclinical animal models of infectious and noninfectious disease and several DNA vaccines have now entered phase I human clinical trials. It is too early to predict the effectiveness of DNA vaccines in humans and whether improved formulations of DNA vaccines will be required but several lines of investigation have suggested ways in which DNA vaccines may be improved, such as increases in expession, facilitation of DNA targeting or uptake, and enhancement of immune responses.     

Minimal model systems for β-sheet secondary structure in proteins

Use of model systems to explore the forces that control β sheet formation was stymied for many years by the perception that small increments of β sheet necessarily aggregate. Recently, however, a number of short peptides (9–16 residues in length) that fold into two-stranded antiparallel β sheets (‘β hairpins’) have been reported; several short peptides (20–24 residues in length) that fold into three-stranded antiparallel β sheets have also been described. These model systems are beginning to provide fundamental insights into the origins of β sheet conformational stability.     

Ionic currents, transmitters and models of motor pattern generators

Recent work, combining direct study of ion channels and synapses with pharmacological manipulations and realistic computer simulations, has deepened our understanding of how motor circuits produce rhythmic outputs. In several preparations, both the roles of some key ionic currents in circuit operation and the mechanisms by which circuit operation may be modulated have been identified.     

The diverse world of coenzyme A binding proteins

Coenzyme A is involved in a number of important metabolic pathways. Recently the structures of several coenzyme A binding proteins have been determined. We compare in some detail the structures of seven different coenzyme A protein complexes. These seven proteins all have distinctly different folds.     

The mechanism and control of cytokinesis

Cytokinesis is under active investigation in each of the dominant experimental model systems. During 1996 and 1997, several developments necessitated the reassessment of the prevailing model for cytokinesis. In addition, the inventory of proteins required for cytokinesis has grown considerably. However, a molecular understanding of cytokinesis still remains elusive.     

Lipid polymorphism and biomembrane function

In recent years, several major developments have taken place in the biology, physical chemistry and technology of polymorphism of membrane lipids. These include the identification of polymorphic regulation of membrane lipid composition in Escherichia coli, the importance of nonbilayer lipids for protein functioning, the special packing properties of bilayers containing these lipids, and the crystalization of a membrane protein out of three dimensional bilayer networks (lipid cubic phases). These exciting developments bring us closer to understanding the paradox of the lipid bilayer structure of biomembranes and the molecular basis of membrane protein structure and function.     

Evolution of the diverse antifreeze proteins

Different types of ice-growth-inhibiting antifreeze proteins, first recognized in fish, have now been isolated from insects and plants, and the list continues to expand. Their structures are amazingly diverse; how they attain the same function are subjects of intense research. Evolutionary precursors of several members have been identified — divergent proteins of apparently unrelated function. The hybridization of information from structural and molecular evolution studies of these molecules provides a forum in which issues of selection, gene genealogy, adaptive evolution, and invention of a novel function can be coherently addressed.     

Novel cofactor derivatives and cofactor-based models

In 1997 and the first half of 1998, numerous publications appeared reporting studies of cofactors and their analogues in classical model systems and in enzyme-catalyzed reactions directed at understanding the enzymatic reactions of their natural cofactors. Model systems based on flavins have provided new insights into enzymatic modulation of the flavin reduction potential, and enzymatic reactions of coenzyme A analogues and derivatives have been employed in several studies of coenzyme A utilizing enzymes. Coenzyme B₁₂ analogues have been utilized as alternate cofactors for B₁₂-utilizing enzymes, while pyrroloquinoline quinone esters and analogues have been employed in model studies of the reactions of quinoprotein-catalyzed reactions.     

Novel metal sites in protein structures

Recently, the three-dimensional structures of several novel metalloenzymes have been solved. Of special interest are those containing uncommon and/or not well characterized metals such as molybdenum, tungsten, nickel, vanadium and cobalt. Modulated by the protein environment, the specific properties of these metals and of special metal-binding cofactors such as siroheme and topa quinone are used to catalyze a vast array of fascinating reactions.     

Archaea: what can we learn from their sequences?

Gene-by-gene and traditional biochemical approaches continue to reveal surprising molecular features in the archaeal domain. In addition, the complete sequencing of several archaeal genomes has further confirmed the phenotypic coherence of these micro-organisms at the molecular level. Nevertheless, the phylogeny of Archaea and the nature of the last universal common ancestor are still matters for debate.     

The metaphase-to-anaphase transition: avoiding a mid-life crisis

The metaphase-to-anaphase transition is a highly regulated process, which is governed by the activity of the anaphase-promoting complex (APC). The APC promotes the degradation of several proteins, including mitotic cyclins and newly identified anaphase inhibitors. Several discoveries made this year shed invaluable light on the regulation of APC activation and its substrate specificity.     

Recent progress in identifying genes regulating hematopoietic stem cell function and fate

Significant advances in the use of genetic and molecular biology strategies have recently begun to identify genes that have a major impact on the determination, commitment and developmental potential of hematopoietic stem cells. Using a variety of experimental strategies, genes such as SCL, GATA-2, HoxB4, Flk-2, c-mpl, dlk, and others have been implicated as important regulators of stem cell growth. In addition, genetic mapping has identified several loci that correlate strongly with stem cell numbers and proliferation.     

Protein-biotin interactions

The three-dimensional structures of several biotin-binding proteins are now known, giving insights into the molecular architecture of the binding sites for biotin. In combination with biochemical and computational approaches, these structural insights provide the basis for our present understanding of biotin—protein interactions which, in some cases, give rise to spectacular binding constants.     

The discovery and validation of new drug targets in cancer

Advances in our understanding of the signal transduction pathways involved in cellular growth control have provided several new strategies for cancer therapy. Recent advances now make it possible to develop selective inhibitors targeting genomic instability, the growth, survival, and invasion of the tumor, and its nourishment through the growth of new blood vessels.     

Plagiarism of the host immune system: lessons about chemokine immunology from viruses

In their attempts to evade the host immune response, mammalian viruses have evolved a wide range of strategies. These include the expression and modification of various host cytokines and receptors. Understanding the mechanism of action of these virally encoded proteins will clearly deepen our insights into immunology. In the past few months several new virally encoded chemokines have been described which can modify both the host immune and antiviral response. Their manipulation of the cytokine structure-function relationship may also be useful in the development of reagents for treating immune and proliferative diseases.     

Solid-phase oligosaccharide synthesis and related technologies

Research efforts directed at the development of methodologies effective for solid-phase synthesis of oligosaccharides have resulted in a number of impressive achievements. In addition, closely related technologies, such as soluble polymer-supported synthesis and fluorous synthesis of the same class of molecules, have proved to be quite promising.     

Antifreeze proteins

Antifreeze proteins comprise a structurally diverse class of proteins that inhibit the growth of ice. Recently, new AFP types have been discovered; more active AFPs have been isolated; antecedents have been recognized supporting the notion of recent, multiple origins; and detailed structures have emerged leading to models for their adsorption to ice     

Do we understand the evolution of genomic imprinting?

The conflict theory is the only hypothesis to have attracted any critical attention for the evolution of genomic imprinting. Although the earliest data appeared supportive, recent systematic analyses have not confirmed the model's predictions. The status of theory remains undecided, however, as post-hoc explanation can be provided as to why these predictions are not borne out.