ISMB 2006
ISMB 2006AB3CX-MeetingISMB 2006
ISMB 2006


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ROBERT HUBER, Max-Planck Institut f. Biochemistry, Martinsried, Germany August, 7


talk title: Molecular machines for protein degradation

abstract: Within cells or subcellular compartments misfolded and/or short-lived regulatory proteins are degraded by protease machines, cage-forming multi-subunit assemblages. Their proteolytic active sites are sequestered within the particles and located on the inner walls. Access of protein substrates is regulated by protein subcomplexes or protein domains which may assist in substrate unfolding dependent of ATP. Five protease machines will be described displaying different subunit structures, oligomeric states, enzymatic mechanisms, and regulatory properties.


SIR TOM BLUNDELL, University of Cambridge August, 7

biosketch: Tom Blundell has been Sir William Dunn Professor of Biochemistry at the University of Cambridge since 1995, and from 1 October 2003 Chairman of the Council of Biological Sciences in Cambridge. After positions in Molecular Biophysics in Oxford and Biochemistry in Sussex Universities, he was appointed in 1976 Professor of Crystallography in Birkbeck College, University of London and in 1989 Honorary Director, Cancer Research Fund Unit of Structural Molecular Biology.

His research interests are in the definition of the architecture of macromolecules and their assemblies and the relation to biological function and diseases including cancer. His research is funded by the Wellcome Trust, BBSRC, MRC and industry. He has published over 400 research papers. Techniques used in his laboratory include biochemistry, protein crystallography and bio-computing. He has used X-ray crystallography to define:

  • Structures of multiprotein complexes involved in DNA repair, including BRCA2 and mutations that occur in breast and other cancers.
  • Conformations of polypeptide hormones, growth factors and their receptors, including work on insulin, glucagon, pancreatic polypeptide, oxytocin, nerve growth factor, hepatocyte growth factor and fibroblast growth factor complex with its receptor
  • Architecture of cellular signalling systems such as protein kinases and their complexes that transduce the intracellular response to growth factors and hormones.
  • Structures of important drug targets such as renin (hypertension) and HIV (AIDS) proteinase.

Tom Blundell has also produced extensive bioinformatics software that includes Composer (written by Sutcliffe in 1987, commercialised via Tripos in 1980s), Modeller (written by Sali in 1991), Fugue (written by Shi and Mizuguchi in 2000), amongst the most widely used top “fold recognition” programs and Crescendo (V Chelliah, 2004) for identification of active sites. These interests have led to work on rational approaches to drug design. He has pioneered methods of structure-based design in 1970s, 1980’s and early 1990’s. Recently he has developed high throughput and fragment-based approaches to drug discovery and co-founded a successful company Astex Therapeutics (see below)

His research work has been recognised by the Gold Medal of Institute of Biotechnology, Krebs Medal of the Federation of European Biochemical Societies, Ciba Medal of Biochemical Society, Feldberg Prize in Biology and Medicine, Alcon Award for Vision Research, the Annual Medal of Society for Chemical Industry and first recipient of the European Award for Innovation in Biomedical Sciences. He is a member of Academia Europaea, a Fellow of the Royal Society and Fellow of Academy of Medical Sciences. He has Honorary Fellowships at Linacre and Brasenose Colleges, Oxford University and at Birkbeck College, London University, and a Professorial Fellowship at Sidney Sussex, Cambridge. He has Honorary Doctorates from fourteen universities.

Tom Blundell has played an active role in national science policy. In the 1980s, he was a member of the advisory group to the Prime Minister (ACOST). He has had a long involvement in the research councils, culminating in his appointment as Director General, Agricultural and Food Research Council (1991 1994) and founding Chief Executive, Biotechnology and Biological Sciences Research Council, BBSRC (1994-1996). He was Chairman of the Royal Commission on Environmental Pollution, 1998 to 2005. He has been President of the UK Biosciences Federation since 2004.

In 1999 Tom Blundell co-founded Astex Technology concerned with the discovery of new medicines and based at the Cambridge Science Park. Their first oncology drug is in clinical trials in USA and UK.

In his spare time, he enjoys walking in Wales, listening to opera and playing jazz. He is married to Dr Bancinyane L Sibanda and has three children: Ricky, Kelesi and Lisa.

talk title: Structural biology, informatics and the discovery of new medicines

abstract: Knowledge of the three-dimensional structures of protein targets now emerging from genomic data has the potential to accelerate greatly drug discovery, but technical challenges and time constraints have traditionally limited their use primarily to target validation and lead optimization. Their application is now being extended into new approaches for lead discovery (for reviews see Blundell et al., 2002; Congreve et al., 2005). Virtual screening coupled with high throughput X-ray crystallography is focused on identifying one or more weakly binding small-molecule fragments from compound libraries consisting of hundreds of small-molecule fragments. The high-resolution definition of this binding interaction provides an information-rich starting point for medicinal chemistry. The use of high throughput X-ray crystallography does not end there, as it becomes a rapid technique to guide the elaboration of the fragments into larger molecular weight lead compounds

One major challenge for drug discovery arises from the very large surfaces that are characteristic of many of the protein complexes, for example those involved in receptor recognition and signal transduction (see for example, Pellegrini et al., 2000). This is especially true of complexes that are assembled from preformed globular domains. Not only is it difficult to bind a small molecule to the large, relatively flat surfaces of such proteins involved in protein interactions, but it is also difficult to disrupt the interaction entirely even if one did. It remains to be seen whether the emerging lead discovery approaches discussed in this lecture will prove suitable for these systems. However, recent analyses of multiprotein systems involved in cell regulation and signalling have identified a large number in which one component involves a flexible or unstructured region of the polypeptide chain. An example involves the complex of the human recombinase, Rad51, and the product of the breast cancer associated gene, BRCA2 (Pellegrini et al., 2003), which is not only scientifically revealing but offers an encouraging and perhaps more druggable site of interaction that could be used to target agents that would be helpful during chemo- or radio-therapy. We suggest that proteins forming interactions with a ligand that comprises a continuous region of flexible peptide may be more druggable targets than where complexes are formed from preformed globular protein structures.


KURT WÜTHRICH, Institute of Molecular Biology and Biophysics ETH Hönggerberg CH-Zürich August, 8

biosketch: Kurt Wüthrich is currently Cecil H. and Ida M. Green Professor of Structural Biology at The Scripps Research Institute, La Jolla, CA, USA and Professor of Biophysics at the ETH Zürich, Zürich, Switzerland. His research interests are in molecular structural biology, and in structural genomics. His specialty is nuclear magnetic resonance (NMR) spectroscopy with biological macromolecules, where he contributed the NMR method of three-dimensional structure determination of proteins and nucleic acids in solution. The Wüthrich groups have solved more than 70 NMR structures of proteins and nucleic acids, including the immunosuppression system cyclophilin A-cyclosporin A, the homeodomain-operator DNA transcriptional regulatory system, and prion proteins from a variety of species.

Kurt Wüthrich was born in Switzerland on October 4, 1938, is married to Marianne Briner, and has two children, Bernhard Andrew and Karin Lynn. He studied chemistry, physics and mathematics at the University of Bern from 57-62, obtained the Eidgenössiches Turn- und Sportlehrerdiplom and a Ph.D. in inorganic chemistry with Prof. Silvio Fallab at the University of Basel in 64, was a postdoctoral fellow in Basel (Prof. S. Fallab), at the University of California in Berkeley, CA, USA (Prof. R.E. Connick) and at Bell Telephone Laboratories in Murray Hill, NJ, USA (Dr. R.G. Shulman) before joining the ETH Zürich in 69 (Privatdozent 70, Assistant Professor 72, Associate Professor 76, Professor of Biophysics 80, Chairman of the Department of Biology 95-00). Since 2001 he shares his time between the ETH Zürich and The Scripps Research Institute. Kurt Wüthrich’s achievements have been recognized by the Prix Louis Jeantet de Médecine, the Kyoto Prize in Advanced Technology, the Nobel Prize in Chemistry, and by a number of other awards and honorary degrees.

talk title: Computational Aspects of NMR Studies with Proteins in Solution

abstract: This lecture will present a survey of selected aspects of solution NMR spectroscopy with proteins. Special empashis will be on the key role of computational methods in NMR data handling, NMR spectral interpretation, calculation of three-dimensional protein structures from NMR data, and most recently attempts to fully automate NMR structure determination of proteins.


MATHIEU BLANCHETTE, ISCB 2006 Overton Prize; McGill University August, 8

biosketch: After being introduced to computational biology by David Sankoff (Université de Montréal), Mathieu Blanchette completed a Ph.D. at University of Washington (1998), under the skilled supervision of Martin Tompa. This was followed by an exciting year in David Haussler's group at UC Santa Cruz, of which he is still reaping the benefits. Since 2003, he is an assistant professor at the McGill Centre for Bioinformatics (School of Computer Science), supervising the work of talented and hard-working students. His main interests revolve around genome evolution and gene regulation, and what can be learned about the latter using the former. The problems that excite him and that he strives to identify and solve are those with a clear mathematical definition, a algorithmically challenging solution, and a practical biological implication.

talk title: What mammalian genomes tell us about our ancestors, and vice-versa.

abstract: This talk will bring together my two passions, genome evolution and gene regulation, and will discuss what the former can teach us about the latter. We have recently shown that the genome of an ancestral mammal living about 70 Million years ago can be computationally reconstructed to a surprising degree of accuracy from the genomes of extant species. In the first part of this talk, I will introduce some of the computational challenges related to the accurate reconstruction of an ancestral genome. I will then describe how this new genome, strategically positioned at the center of the mammalian radiation, allows a detailed study of the evolution of transcriptional regulatory regions. Finally, I will describe how whole-genome analyses based in part on comparative genomics reveal new and unexpected traits of mammalian regulatory regions, both those located in non-coding regions and those hiding within protein-coding DNA. The work presented is the result of collaborations with David Haussler, Webb Miller, and François Robert.


ELENA CONTI , EMBL Heidelberg August, 9

biosketch: Elena Conti trained as a chemist in Pavia (Italy) and received her Ph.D. in Biophysics at Imperial College (London) where she studied protein crystallography. She then joined the laboratory of John Kuriyan at the Rockefeller University in New York, where she became interested in the molecular mechanisms that govern the transport of nuclear proteins and RNAs from their site of synthesis to their site of function in eukaryotic cells. In 1999 she moved to EMBL (Heidelberg), in the Structural and Computational Biology Unit. Her research has expanded from the study of nucleo-cytoplasmic transport to its connections to upstream and downstream processes, in particular the link between mRNA export and mRNA processing, surveillance and decay. The focus of her group is to understand these basic cell biology problems at the atomic level. Since January 2006, Elena has been appointed Director at the Max Planck Institute of Biochemistry (Martinsried, Munich), heading the ‘Structural Cell Biology’ department.

talk title: Molecular mechanisms in RNA degradation

abstract: The life span of RNAs in the cell depends on the balance between the rate in which they are synthesized and the rate with which they are degraded. For coding RNAs, degradation is rather slow in the case of gene products with housekeeping functions, and is fast in the case of aberrant mRNAs that need to be rapidly destroyed before being translated into aberrant proteins. Nonsense-mediated mRNA decay is a surveillance pathway that detects and degrades mRNA with premature stop codons (PTCs). PTCs can arise from alternative splicing, from defects in mRNA processing, and are also present in an estimated 30% of inherited genetic disorders. The talk will focus on our current understanding of the molecular mechanisms of this mRNA surveillance and degradation pathway.


CHARLES DELISI, Boston University August, 9

biosketch: Charles DeLisi is the Metcalf Professor of Science and Engineering at Boston University, and also served as Dean of the College of Engineering from 1990-2000. Prior to moving to BU, he was Professor and Chair of Biomathematical Sciences and Professor of Molecular Biology at the Mount Sinai Medical School (1987-1999), Director of the Department of Energy's Health and Environmental Research Programs (1985-1987), Section Chief at NIH (1975-1985), and Theoretical Division Staff Scientist at Los Alamos National Laboratory (1972-1975). In 1999 he initiated the BU graduate program in Bioinformatics, which now includes approximately 120 students and 50 faculty from across the University. He also co-Directs the Center for Advanced Biotechnology and is the University’s Senior Associate Provost for Biosciences.

Dr DeLisi is co-founder of two Biotech start-ups--Pharmadyne Inc, which combines immunology and genomics to develop anti viral diagnostics and therapeutics, and Boston Array technologies, which is focused on high throughput proteomics. He has authored or coauthored more than 250 scientific papers and is recipient of numerous awards including the Presidential Citizens Medal, awarded to him by President Clinton for his seminal role in initiating the Human Genome Project.

talk title: New Approaches to Biomarker Discovery

abstract: We discuss a series of computational and experimental screens designed to efficiently locate disease associated epigenetic changes in regulatory regions. Preliminary findings are discussed for renal cell carcinoma


RICHARD J. ROBERTS, New England Biolabs August, 10


talk title: The need of Bioinformatics for experimental biologists

abstract: I hope that the audience, being predominantly computational people, can be convinced of the need to engage the experimentalists directly rather than waiting for some biochemist to read their work and offer to help by chance. I feel quite strongly that without more emphasis on experimental follow up there is little point in generating more sequences and more predictions. However, it won't be a tale of doom for computational biology, but rather a call for the community to help itself with some specific ideas of how to do so.


MICHAEL WATERMAN, ISCB 2006 Sr. Scientist Accomplishment Award; University of Southern California August, 10

biosketch: Michael S. Waterman obtained a bachelor’s in mathematics from Oregon State University and a doctorate in statistics and probability (1969) from Michigan State University, then began his academic career at Idaho State University. . He was invited to spend several summers at Los Alamos National Laboratory in the early 1970s. He began to collaborate with Temple Smith, also a visitor to the lab, where their fellow scientists and friends included Stanslaw Ulam, Nick Metropolis, Marc Kac, and Gian-Carlo Rota. One result was the Smith-Waterman algorithm for determining the degree of similarity (homology) of amino acid sequences from DNA, RNA, or proteins. In a three-page paper, published in the Journal of Molecular Biology in 1981, Waterman and Smith launched a large part of the bioinformatics revolution. Waterman joined the staff at Los Alamos in 1975, then moved to the University of Southern California in 1982. He has been honored as a USC Professor and holds the USC Associates Endowed Chair in the Natural Sciences. He is a member of the National Academy of Sciences and was elected to the French Académie des Sciences in 2005. He is also a Fellow of AAAS and a professor-at-large in the Keck Graduate Institute of Life Sciences. In 2003, Prof. Waterman became Faculty Master of Parkside International Residence College at USC, which is home to 600 students and is an international center. He is a founding editor of the Journal of Computational Biology, an editor for six other major journals, and one of the fathers of the RECOMB annual meetings. He is author of more than 150 journal articles and author or co-author of several textbooks, of which the latest (written with Richard C. Deonier and Simon Tavaré), is Computational Genome Analysis: An Introduction (Springer, 2005).

talk title: Whole Genome Optical Mapping

abstract: An innovative new technology, optical mapping, is used to infer the genome map of the location of short sequence patterns called restriction sites. The technology, developed by David Schwartz, allows the visualization of the maps of randomly located single molecules around a million base pairs in length. The genome map is constructed from overlapping these shorter maps. The mathematical and computational challenges come from modeling the measurement errors and from the process of map assembly.


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