Research Groups

Kurt Anderson
Actin Dynamics
Jeff Evans
Translational Cancer Therapeutics
David Gillespie
Checkpoints and Cell Cycle Control
Eyal Gottlieb
Apoptosis and Tumour Metabolism
Danny Huang
Ubiquitin Signalling
Gareth Inman
Growth Factor Signalling
Robert Insall
Cell Movement and Chemotaxis
Frank Kozielski
Molecular Motors
Hing Leung
Urology Research
Laura Machesky
Actin in Cell Migration, Invasion and Metastasis
Jim Norman
Integrin Cell Biology
Michael Olson
Molecular Cell Biology
Brad Ozanne
Invasion and Metastasis
Kevin Ryan
Understanding Cell Death in Tumour Cells
Owen Sansom
Colorectal Cancer and WNT Signalling
Marcos Vidal
Drosophila Approaches to Cancer
Karen Vousden
Tumour Suppression
Robert J White
Transcription and Cancer
Frank Kozielski - Molecular Motors

Introduction

Frank KozielskiKinesins form a superfamily of proteins that fulfil key roles in intracellular transport and cell division. They use the energy derived from ATP hydrolysis to transport a variety of cargos directionally along microtubules but are also involved at crucial phases of the eukaryotic cell cycle, including bipolar spindle formation, chromosome congression, anaphase and cytokinesis. We are examining human kinesins with a focus on mitotic motors and their associated proteins.

The overall goal of our research is to develop and apply interdisciplinary approaches to identify new inhibitors and improve existing ones with the aim of developing these molecules as future chemotherapeutics. We will determine the structures of kinesins, both alone and in complex with inhibitors, DNA and/or associated proteins.

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Lab Report
Link to Kozielski Scientific Report 2008 Link to Kozielski Scientific Report 2008 131.66 Kb

Key Publications

Garcia-Saez I, DeBonis S, Lopez R, Fernando Trucco F, Rousseau B, Thuery P, Kozielski F (2007). Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration. J Biol Chem. 282, 9740-7.

Kozielski F, DeBonis S, Buhrmeister WP, Cohen-Addad C, Wade RH (1999). The crystal structure of the minus-end-directed microtubule motor protein ncd reveals variable dimer conformations. Structure 7, 1407-16.

Kozielski F, Sack S, Marx A, Thormählen M, Schönbrunn E, Biou V, Thompson A, Mandelkow E-M, Mandelkow E (1997). The crystal structure of dimeric kinesin and implications for microtubule-dependent motility. Cell 91, 985-94.

Biography
Education and qualifications
1997: PhD, University of Hamburg, Supervisor Christian Betzel
1978: BSc, Chemistry (First Class Honours), University of Hamburg

Appointments
2007-present: Group Leader, Beatson Institute for Cancer Research
2005-2007: Group Leader, French Atomic Commission, CEA/IBS, Grenoble, France
2001-2005: Team Leader, CEA/IBS, Grenoble, France
1999-2001: Research Scientist (tenured) with Richard Wade, CEA/IBS, Grenoble, France
1997-1999: Postdoctoral Fellow with Richard Wade, IBS, Grenoble, France

Committee membership
2006-present: French Society for Therapeutic Chemistry

Recent Publications
Kaan HY, Ulaganathan V, Hackney DD, Kozielski F (2009). An allosteric transition trapped in an intermediate state of a new kinesin-inhibitor complex. Biochem J., in press.

Tcherniuk S, van Lis R, Kozielski F, Skoufias DA (2009). Mutations in the human kinesin Eg5 confer resistance to monastrol and STLC in tumour derived cell lines. Biochem Pharmacol., in press.

Putey A, Popowycz F, Do QT, Bernard P, Talapatra SK, Kozielski F, Galmarini CM, Joseph B (2009). Indolobenzazepin-7-ones and 6-, 8-, and 9-membered ring derivatives as tubulin polymerization inhibitors: synthesis and structure-activity relationship studies. J Med Chem. 52, 5916-5925.

Koehler CJ, Strozynski M, Kozielski F, Treumann A, Thiede B (2009). Isobaric peptide termini labeling for MS/MS-based quantitative proteomics. J Proteome Res. 8, 4333-41.

Comas H, Buisson D-A, Najman R, Kozielski F, Roussequ B, Lopez R (2009). Synthesis of 5-acyl-3,4-dihydropyrimidine-2-thiones via solvent-free solution phase and solid phase Biginelli procedures. Synlett 11, 1737-40.

Peris L, Wagenbach M, Lafanechère L, Brocard J, Moore AT, Kozielski F, Job D, Wordeman L, Andrieux A (2009). Motor-dependent microtubule disassembly driven by tubulin tyrosination. J Cell Biol. 185, 1159-66.

Popowycz F, Schneider C, Debonis S, Skoufias DA, Kozielski F, Galmarini CM, Joseph B (2009). Synthesis and antiproliferative evaluation of pyrazolo[1,5-a]-1,3,5-triazine mtoseverin derivatives. Bioorg Med Chem. 17, 3471-8.

Wade RH, Garcia-Saez I, Kozielski F (2009). Structural variations in protein superfamilies: actin and tubulin. Mol. Biotechnol. 42, 49-60.

Debonis S, Skoufias DA, Indorato RL, Liger F, Marquet B, Laggner C, Joseph B, Kozielski F (2008). Structure-activity relationship of S-trityl-L-cysteine analogues as inhibitors of the human mitotic kinesin Eg5. J Med Chem. 51, 1115-25.

Kozielski F, Skoufias DA, Indorato RL, Saoudi Y, Jungblut PR, Hustoft HK, Strozynski M, Thiede B (2008). Proteome analysis of apoptosis signaling by S-trityl-L-cysteine, a potent reversible inhibitor of human mitotic kinesin Eg5. Proteomics 8, 289-300.

Garcia-Saez I, DeBonis S, Lopez R, Fernando Trucco F, Rousseau B, Thuery P, Kozielski F (2007). Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration. J Biol Chem. 282, 9740-7.

Kozielski F, DeBonis S, Skoufias DA (2007). Screening for inhibitors of microtubule-associated motor proteins. Methods in Mol Med. 13, 189-207.

Klein E, DeBonis S, Skoufias DA, Kozielski F, Lebeau L (2007). New chemical tools for investigating human mitotic kinesin Eg5. Bioorg Med Chem. 15, 6474-88.

Brier S, Carletti E, DeBonis S, Hewat E, Lemaire D, Kozielski F (2006). The marine natural product adociasulfate-2 as a tool to identify the MT-binding region of kinesins. Biochem. 45, 15644-53.

Skoufias DA, DeBonis S, Lebeau L, Crevel I, Saoudi Y, Cross R, Wade RH, Hackney D, Kozielski F (2006). S-trityl-L-cysteine is a reversible, tight-binding inhibitor of the human kinesin Eg5 that specifically blocks mitotic progression. J Biol.Chem. 281, 17559-69.

Brier S, Lemaire D, DeBonis S, Forest E, Kozielski F (2006). Molecular dissection of the inhibitor binding pocket of human mitotic Eg5 reveals mutants that confer resistance to antimitotic agents. J Mol Biol. 360, 360-76.

Neumann E, Garcia-Saez I, DeBonis S, Wade RH, Kozielski F, Conway JF (2006). Human kinetochore-associated kinesin CENP-E visualized at 17 Å resolution bound to microtubules. J Mol Biol. 362, 203-11.

Banci L, Bertini I, Cusack S, de Jong RN, Heinemann U, Jones EY, Kozielski F, Maskos K, Messerschmidt A, Owens R, Perrakis A, Potersman A, Schneider G, Siebold C, Silman I, Sisma T, Stewart-Jones G, Sussman JL, Thierry J-C, Moras D (2006). First steps towards effective methods in exploiting high-throughput technologies for the determination of human protein structures of high biomedical value. Acta Cryst. D 62, 1208-17.

Garcia-Saez I, Tcherniuk S, Kozielski F (2006). The structure of human neuronal Rab6B in the active and inactive form. Acta Cryst. D 62, 725-73.

Videos and Images


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