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Project Guidelines

1. Survey the contribution of the sequencing of pathogenic bacterial genomes to the understanding of mechanisms of disease and the development of novel antibiotics.

2. Survey the range of "proteinopathies" that occur with increasing age. Discuss the functional roles of a few vulnerable proteins that are known to lead to these protein deposition diseases and outline current theories of why they form deposits or inclusions.

3. Describe the structures and functions of porins. Highlight one example from a bacterium and one from a vertebrate.

4. All vertebrate eye lenses contain families of alpha-, beta- and gamma-crystallins. Review what is known of their 3D structures and biophysical properties. What features make them suitable for their long life in the eye lens? What kinds of chemical and conformational changes are associated with human cataract?

5. Compare progress in the structure determination of the three types of cytoskeletal filaments. Survey the roles these different filaments play in human disease.

6. Describe a number of important examples of how symmetry can contribute to the structure, function and stability of proteins, citing example structures in each case.

7. Survey the range of functions that rely on recognition of DNA by a protein. Give examples of how defects in protein-DNA recognition can cause human disease and explain the structural principles of each.

8. Survey the range of protein structures that are found on the cell surface in prokaryotes and eukaryotes. Describe in detail the structure and function of one example from each kingdom that is important in human disease.

9. Evaluate our current understanding of protein stability. Describe how our knowledge of protein structures from thermophilic organisms have contributed to this debate.

10. One of the most important recent advances in structural biology has been the elucidation of the structure of the ribosome. Describe in detail what we now know of the structures of bacterial ribosomes. By comparing these structures with those of eukaryotic ribosomes, explain what makes the ribosome a good target for antibacterial drug design..

11. Survey the structures of lipases and phospholipases and their interactions with their substrates at the proteins' active sites. Explain how defects in these proteins can cause human disease.

12. Evaluate and compare the holdings of the protein domain databases Pfam, ProDom and SMART in terms of their coverage, ease of use, depth of coverage of each protein family, and the accuracy of the information provided.

13. Survey the structures and functions of all proteins of known structure from the influenza virus. How are these proteins being targeted in antiviral drug design, particularly in the light of recent epidemics of H5N1 avian flu and H1N1 swine flu?

14. Survey the structures of proteins in the haemoglobin family still available in the PDB, from the earliest to the most recent. How have the more recent structures contributed to our understanding of the evolution and mechanism of action of these proteins, and of diseases such as sickle cell anaemia and the thalassemias?

15. Survey and evaluate in detail the range of structures in the PDB that include amino-aromatic and/or pi-stacking interactions between ligands and protein binding site residues. How have these types of interaction been used in drug design?

16. Discuss the biological role of the exosome and relate this to the structural details of the macromolecular cage utilized in the controlled degradation of RNA.

17. Blood clotting requires a number of protein factors to respond to bleeding events. Describe the structures, functions and mechanisms of proteins involved in this cascade, focusing particularly on the role of tissue factor.

18. Viruses use symmetry to derive complete structures from a tiny amount of genetic material. Survey a comprehensive range of known three-dimensional structures of virus particles, illustrating and explaining in detail in each case how the symmetry is built up.

19. Fixing carbon is an essential process for higher life to survive. Describe in detail the structure of the enzyme RUBISCO and explain how its structural features allow this highly specific catalytic event to occur in plants.

20. Survey the range of structures of proteins from the malarial parasite Plasmodium falciparum. How are these proteins being targeted in the design of drugs against malaria?

21. Describe in detail the structures of proteins involved in nucleic acid transcription. Pay particular attention to the similarities and differences in structure between DNA polymerase and reverse transcriptase, relating this, wherever possible, to some of the successes and challenges in anti-HIV drug design.

22. Discuss the production of oxytocin from gene to active hormone. Include discussions of the structural information for the isolated hormone, the carrier protein neurophysin and bound complexes of the two as the gene product is processed biologically.

23. Aminoacyl-tRNA synthetases must operate with a high fidelity. Justify this statement in terms of the structural differences found in a series of solved synthetases for different amino acids.

24. Describe some of the structures solved through the M. tuberculosis structural genomics project and use these to evaluate the contribution made by this project to drug discovery.

25. Describe recent progress in the 3D structure determination of members of the G-protein coupled receptor family (also known as serpentine receptors). How can these studies contribute to drug discovery?

26. Survey the structures of proteins that bind ATP. Discuss from a structural perspective the range of biological processes that use this type of protein recognition.

27. Describe a representative protein kinase in detail. Survey the detailed structures and functions of the proteins in the human kinome. How is this information used to design specific drugs, particularly against cancer?

28. Describe how structures of proteins in the human immune system, and particularly MHC structures, are being used in vaccine design. How far, at our current state of knowledge, can this information being applied to the design of animal vaccines against, for example, the parasitic cattle disease East Coast Fever?

29. Describe in detail the events involved in the human innate immune response, focusing on the structures and mechanisms of action of complement proteins, cytokines and other proteins involved in this response.

30. Discuss the structures and functions of the circadian clock proteins from cyanobacteria. How do the structures of these proteins determine their function?

31. Discuss the structures and functions of the enzymes that form the biphenyl biodegradation pathway in bacteria. What is the potential for the use of this process for removal of polychlorinated biphenyls (PCBs) contamination in the environment?

32. Using human genes and proteins as examples, describe the role of gene duplication in the evolution of protein structure and function. Your answer should include examples of single domain and multi-domain protein chains, protein monomers and oligomers and protein families.

33. The bacterium Helicobacter pylori has now been implicated in the development of chronic gastritis and stomach cancer. Survey the structures of a range of proteins from the proteome of this bacterium, explaining, where appropriate, how the proteins you describe are involved in the pathogenesis of these conditions.

34. Lysozyme is one of the most stable proteins when crystallised and was one of the first to have its structure determined. Describe and explain how studies of this protein have contributed to technical developments in structural and molecular biology, focusing particularly on X-ray crystallography and site-directed mutagenesis.

35. Green fluorescent protein can be engineered to have many colours and many potential uses. Discuss the structure, how it was modified and applications of these various forms.

36. Cryoprotectants allow organisms to resist freezing and the formation of ice crystals if the temperature moves to below freezing. Survey the different structural solutions found by fish and insects to prevent damage due to extreme cooling.

37. Ribonucleases are toxic to cells and were considered as a treatment for cancer. Survey this structural family and discuss how this damaging molecule is contained in the cell and why it proved not to be useful in cancer treatment.

Please refer to the project guidelines before choosing your project.