Cyclin-dependent kinases trigger and coordinate transitions between different phases the cell division cycle (CDK1, 2, 3, 4, 6, 7). They also play a role in apoptosis (CDK2), in neuronal cells (CDK5) and in the control of transcription (CDK 7, 8, 9). Intensive screening has lead to the recent identification of a series of chemical inhibitors of CDKs: olomoucine, roscovitine, purvalanol, CVT -313, flavopiridol, y butyrolactone, indirubins, paullones and staurosporine. Some of these compounds display remarkable selectivities and efficiencies (IC5o < 25 nM). Many have been co-crystallised with CDK2 and their interactions with the kinase have been analysed in atomic detail. These inhibitors all act by competing with ATP for binding at the catalytic site. Most inhibitors present a flat heterocyclic ring system that occupies the purine binding pocket as well as form 2 or 3 hydrogen bonds with Glu-81 and Leu-83. The binding modes of these inhibitors are reviewed in this article. Knowledge of the CDK/inhibitor interactions will be of great help to design inhibitors with improved selectivity our potency as well as to generate affinity chromatography matrices for the purification and identification of their cellular targets. The potential use of CDK inhibitors is being extensively evaluated in cancer chemotherapy and other fields such as the cardiovascular domain (restenosis), dermatology (psoriasis), nephrology (glomerulonephritis) parasitology (unicellular parasites such as Plasmodium, Trypanosomes, Toxoplasm,...etc.), neurology (Alzheimer's disease) and viral infections (cytomegalovirus, H.I.V., herpes).
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Advances in quantum structure science and technology have proceeded in a remarkable manner over the past few years. In addition to basic science issues, imminent applications are occurring in fields as varied as quantum computing and biological sensors and manipulation. It has been stated that nano-structures are able to provide the most perfect crystals, free of impurities, defects and strain. The positron (anti-particle of the electron) appears to be an exquisitely sensitive probe of the quality of nano-structure and in the case of semiconductors, the electronic structure. Electron-positron annihilation produces two collinear γ -rays of equal energy (0.511 MeV) in vacuum and in the rest frame. In a real material the γ rays are slightly momentum Doppler shifted due to the momentum of the electron with which the positron is annihilating. By measuring these Doppler shifts one obtains information about the electronic momentum density. Additionally, the lifetime of the positron in a material is dictated by the electron density in the vicinity of the positron. Data are presented from a variety of quantum systems with emphasis on our measurements on CdSe quantum dots. A model and theory in support of our measurements will also be presented. This model predicts the smearing of the electronic momentum density at the boundary of the Jones zone proportional to the widening of the band gap as the quantum dot size decreases. Keywords: QUANTUM STRUCTURES, POSITRON ANNIHILATION SPECTROSCOPY, ELECTRONIC STRUCTUREActa Cryst. (2002 The retinoblastoma tumor suppressor protein (pRb) regulates the cell cycle, sponsors differentiation and restrains apoptosis. Dysfunctional pRb is thought to be necessary for the development of most human malignancies. As many of the anti-tumorigenic properties of pRb are mediated by its regulation of the E2F transcription factors, we have determined the crystal structure of a fragment of E2F (residues 409-426) bound to pRb. It reveals how E2F acts as a structural sensor of pRb integrity and illuminates the role played by these two proteins in the regulation of apoptosis. We also show that the binding of E2F (409-426) The lethal form of human malaria is caused by the protozoal parasite Plasmodium falciparum, and may be responsible for 1.5 million deaths per year. The lack of an effective vaccine means that there is an urgent need for novel approaches to prophylaxis and treatment. One such approach is the development of drugs that interfere with P. Falciparum cell-cycle regulation. In eukaryotic organisms where it has been studied, cell proliferation is controlled by the action of cyclin dependent kinases (CDKs). Activity of these enzymes is in turn controlled by a network of regulatory interactions and covalent modifications. We are studying CDK-containing complexes of P. Falciparum in order a) to characterize the extent to which P. Falciparum follows previously identified structural paradigms of cell-cycle regulation, and b) to facilitate the structure-based design of specific P. Falciparum CDK inh...
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