The SBCG Group

The work of SBCG addresses structural aspects of a number of diverse biological issues that include signal transduction pathways, enzyme mechanism, proteins of the inflammatory response and enzymes of biotechnological interest for the purpose of structure-based design of small molecules, substrates or inhibitors.

Members

• Dr. Nikos G. Oikonomakos, Director of IOPC
• Dr. Demetres D. Leonidas, Researcher B'
• Dr. Spyros E. Zographos, Researcher C'
• Dr. Evangelia D. Chrysina Researcher
• Dr. Eliada Lazoura, Research Fellow (GSRT/ENTER 2006-2008)
• Dr. Joe Hayes, Research Fellow (DRUGDESI-European TOK, 2007-2009)
• Ms. Kyra Melinda Alexacou, Ph.D. student (EURODESY-European EST, 2006-2009)
• Mr. Dimitris Papageorgiou, MSc student
• Ms. Chrysa Kyritsi, MRes student
• Mr. Dimitris Sovantzis, MRes student
• Ms. Eirini Markella Antoniou, final year research project student
• Ms. Vasilleia Kouneli, final year research project student
• Ms. Maria Daskalaki, final year research project student
• Ms. Ifigeneia Bosmi, final year research project student

Group Pages

Current Recent Projects

- Control of glycogen metabolism
Glycogen phosphorylase inhibitors as potential antidiabetic drugs. The development of glycogen phosphorylase inhibitors has been the focus of much effort to find new compounds to treat type 2 diabetes.
Structure and function of phosphorylase kinase. Phosphorylase kinase plays a significant role in the metabolism of glucose, interference with this function is of interest for the development of potential anti-diabetic drugs.

- Calcium/calmodulin regulated kinase family [Research Training network HPRN-CT-2002-00252 (2002-2006)]
Calmodulin regulated protein kinases: molecular and cellular function of five protorypic members from the human genome by a multidisciplinary approach. The project will combine bioinformatics approaches, investigation of their molecular structures, the identification of their physiological substrates to decipher their roles in biological processes, and investigations of the underlying molecular mechanisms for their activation and catalytic activities. The network objectives will be directed towards applications of these kinases as putative targets for the discovery of compounds leading to the development of specific drugs to cure these kinase-associated diseases (coordinator: Dr. Matthias Wilmanns, EMBL, head of the EMBL Outstation at the DESY synchrotron site, Hamburg, Germany).

- RNases
Rational Design of Ribonuclease Inhibitors. Multiple avenues toward a long-term goal, the design of drugs to control tumour angiogenesis, allergic reactions and viral replication, using the rational drug design approach, based on the high resolution crystal structures of various RNase homologues.

- Carbohydrate recognition
Structural basis of carbohydrate recognition by lectins. Lectins are a superfamily of carbohydrate-specific proteins that mediate cellular recognition. Knowledge about the carbohydrate recognition domains of lectins, is important in understanding their carbohydrate specificity and in elucidating their role(s) in cellular recognition events.

- Control of neuromuscular transmission
Structural Basis of Nicotinic Acetylcholine Receptor Function. The aim of the project is the determination of the 3-D structure of the neurotransmitter receptor, nicotinic acetylcholine receptor (AChR), at high resolution, in order to understand the structural basis of its function, using advanced electron microscopy (EM), NMR, atomic force microscopy (AFM) and X-ray crystallographic methods, combined with monoclonal antibody and ligand labelling (coordinator: Prof. Socrates Tzartos, Dept. of Pharmacy, University of Patras, Hellenic Pasteur Institute, Athens, Greece).

- Structure/function relationship in recombinant human TAFs9 proteins
The central aim of this project is to achieve the structural and functional characterisation of the human proteins TAFII31 and hCIP1, that are encoded as alternatively spliced transcripts of the TAF9 genomic locus. Elucidating the biological function of these proteins is of great interest, as they may be key molecules linking the basal transcription machinery and aspects of pre-mRNA metabolism, and because of their possible involvement in neurodegenerative pathway (In collaboration with Prof. Niovi Santama, Dept. of Biological Sciences, University of Cyprus, Cyprus, Prof. C. Sakarellos, Dept. of Chemistry, University of Ioannina, Greece, and Prof. Angus Lamond, Wellcome Trust Biocentre, University of Dundee, UK).

- Xylanases and feruloyl esterases
Xylanases F10 and F11 and Type A and Type B feruloyl esterases. Crystallisation and co-crystallisation of alkaline xylanase family 10 from Fusarium oxysporoum with branched xylose-oligosaccharides and structure determination for commercial application in pulp and paper industry (in collaboration with Prof. P. Christakopoulos, Biotechnology Laboratory, Dept. of Chemical Engineering, National Technical University of Athens, Greece).

National Collaborations

Prof. Paul Christakopoulos, Dept. of Chemical Engineering, National Technical University of Athens
Prof. Athanasios Gimisis, Dept. of Chemistry, Univ. of Athens
Prof. Elias Eliopoulos, Dept. of Agricultural Biology & Biotechnology, Agricultural University of Athens
Prof. Fragiskos N. Kolisis, Dept. of Chemical Engineering, National Technical University of Athens
Dr. Avgi Mamalaki, Dept. of Biochemistry, Hellenic Pasteur Institute
Dr. Irene Mavridis, Institute of Physical Chemistry, NCSR ''Demokritos'', Athens
Prof. Costantinos Sakarellos, Dept. of Chemistry, Univ. of Ioannina
Prof. A. Siafaka-Kapadai, Dept. of Chem. Biochem., Univ. of Athens
Prof. Leandros Skaltsounis, Dept. of Pharmacy, Univ. of Athens
Prof. Socrates J. Tzartos, Dept. of Pharmacy, Univ. of Patras

International Collaborations

Prof. George Archontis, Dept. of Physics, Univ. of Cyprus
Prof. Mikael Bols, Dept. of Chemistry, University of Aarhus, Denmark
Dr. Jagmohan Singh Bains, Dept. of Molecular Biology and Biochemistry, Guru Bbak Dev University, Amritsar, India
Prof. Gerhard Eisenbrand, Fachbereich Chemie, Univ. Kaiserslautem, Germany
Prof. George W. J. Fleet, Dyson Perrins Laboratory, University of Oxford, UK
Prof. Mathias Gautel, Muscle Cell Biology, The Randall Centre, King's College, London, UK
Prof. Pal Gergely, Dept. of Medical Chemistry, Univ. of Debrecen, Hungary
Prof. Athanassios Giannis, Institut fuer Organische Chemie, Univ. Leipzig, Germany
Prof. Dame Louise N. Johnson, F.R.S. Laboratory of Molecular Biophysics, University of Oxford, UK
Prof. Martin Karplus, Dept. of Chemistry and Chemical Biology, Harvard Univ., Cambridge, MA, USA
Prof. D. Loganathan, Dept. of Chemistry, Indian Institute of Technology, Madras, India
Prof. Alexander D. Mackerell, Jr., Computer-Aided Drug Design Center, School of Pharmacy, Univ. of Maryland, Baltimore
Dr. Josef Matousek, Inst. of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, Libechov, Chech Rebublic
Prof. P. Pouckova, Dept. of Radiology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
Dr. E. Boix, Dept. of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Barcelona, Spain
Dr. S. Dasgupta, Dept. of Chemistry, Indian Institute of Technology, Kharagpur, India
Prof. T. B. Ng, Dept. of Biochemistry, The Chinese University of Hong Kong, Hong Kong, China
Dr. Jean-Pierre Praly, Claude-Bernard University, Lyon, France
Dr. Niovi Santama, Molecular Biology & Biochemistry Lab, Univ. of Cyprus, Nicosia
Prof. Laszlo Somsak, Dept. of Organic Chemistry, Univ. of Debrecen, Hungary
Dr. B.M. Swamy, Dept. of Biochemistry, Karnatak University, India
Prof. Andrea Vasella, Lab. for Organische Chemie, ETH-Zentrum, Zorich, Switzerland
Prof. Mauno Vihinen, Institute of Medical Technology, University of Tampere, Finland
Dr. Matthias Wilmanns, Head of EMBL Outstation at the DESY, Hamburg, Germany,
Dr. Giuseppe Zagotto, Dept. of Pharmaceutical Sciences, University of Padova, Italy

Recent Publications (with PDB codes)


Oikonomakos, N.G., Schnier, J.B., Zographos, S.E., Skamnaki, V.T., Tsitsanou, K.E., and Johnson, L.N. (2000). Flavopiridol inhibits glycogen phosphorylase by binding at the inhibitor site. J. Biol. Chem. 275, 34566-34573. {PDB code: 1C8K}

Oikonomakos, N.G., Skamnaki, V.T., Tsitsanou, K.E., Gavalas, N.G., and Johnson, L.N. (2000). A new allosteric site in glycogen phosphorylase b as a target for drug interactions. Structure 8, 575-584. {PDB code: 1C50}

Kontou, M., Leonidas, D.D., Vatzaki, E.H., Acharya, K.R., Mamalaki, A., Oikonomakos, N.G., and Tzartos, S.J. (2000). The crystal structure of a Fab fragment of a rat monoclonal antibody against the main immunogenic region of the human muscle acetylcholine receptor. Eur. J. Biochem. 267, 2389-2396. {PDB code: 1C5D}

Tsitsanou, K.E., Skamnaki, V.T., and Oikonomakos, N.G. (2000). Structural basis of the synergistic inhibition of glycogen phosphorylase a by caffeine and a potential antidiabetic drug. Arch. Biochem. Biophys. 384, 245-254. {PDB code: 1C8L}

Skamnaki, V.T., Oikonomakos, N.G. (2000). Kinetic characterization of the double mutant R148A/E182S of glycogen phosphorylase kinase catalytic subunit: the role of the activation loop. J. Protein Chem. 19, 499-505.

Poulas K, Eliopoulos E., Vatzaki E., Navaza J., Kontou M., Oikonomakos N., Acharya K.R., Tzartos S.J. (2001). Crystal structure of Fab198, an efficient protector of the acetylcholine receptor against myasthenogenic antibodies. Eur. J. Biochem., 268, 3685-93. {PDB code: 1FN4}

Oikonomakos, N.G., Skamnaki, V.T., Osz, E., Szilagyi, L., Somsak, L., Docsa, T., Toth, B. and Gergely, P. (2002). Kinetic and crystallographic studies of glucopyranosylidene spirothiohydantoin binding to glycogen phosphorylase b. Bioorg. Med. Chem. 10, 261-268. {PDB code: 1HLF}

Oikonomakos, N.G., Zographos, S.E., Skamnaki, V.T. and Archontis, G. (2002). The 1.76 A resolution crystal structure of glycogen phosphorylase b complexed with glucose, and CP320626, a potential antidiabetic drug. Bioorg. Med. Chem. 10, 1313-1319. {PDB code: 1H5U}

Oikonomakos, N.G., Kosmopoulou, M., Zographos, S.E., Leonidas, D.D., Chrysina, E.D., Somsak, L., Nagy, V., Praly, J.P., Docsa, T., Toth, B. and Gergely, P. (2002). Binding of N-acetyl-N'-beta-D-glucopyranosyl urea and N-benzoyl -N'-beta-D-glucopyranosyl urea to glycogen phosphorylase b: kinetic and crystallographic studies. Eur. J. Biochem. 269, 1684-1696. {PDB codes: 1K06, 1K08, 1KTI} Cover Story

Cook, A., Lowe, E.D., Chrysina, E.D., Skamnaki, V.T. Oikonomakos, N.G. and Johnson, L.N. (2002). Structural studies of Phospho-CDK2/Cyclin A bound to nitrate, a transition state analogue: Implications for the protein kinase mechanism. Biochemistry 41, 7301-7311. {PDB code: 1GY3}

Oikonomakos, N.G. (2002). Glycogen phosphorylase as a molecular target for type 2 diabetes therapy. Curr Protein Pept Sci. 3, 561-586. Cover Story

Oikonomakos N.G, Chrysina, E.D., Kosmopoulou, M.N. and Leonidas, D.D. (2003) Crystal structure of rabbit muscle glycogen phosphorylase a in complex with a potential hypoglycaemic drug at 2.0 ? resolution. (2003) Biochim. Biophys. Acta 1647, 325-332. {PDB codes: 1LWN, 1LWO}

Leonidas, D.D., Swamy, B.M., Bhat, A.G., Inamdar, S.R., Kosmopoulou, M.N., Chrysina, E.D., and Oikonomakos, N.G. (2003) Crystallization and preliminary X-ray crystallographic analysis of Sclerotium rolfssii lectin. Acta Cryst. D59, 363-365.

Chrysina, E.D., Oikonomakos, N.G., Zographos, S.E., Kosmopoulou, M.N., Bischler, N., Leonidas, D.D., Kov?cs, L., Docsa, T., Gergely, P., and Soms?k L. (2003) Crystallographic studies on alpha- and beta-D-glucopyranosyl formamide analogues, inhibitors of glycogen phosphorylase. Biocatal. & Biotransfor. 21, 233-242. {PDB codes: 1P4G, 1P4H, 1P4J}

Pinotsis, N., Leonidas, D.D., Chrysina, E.D., Oikonomakos, N.G., and Mavridis, I.M. (2003). The binding of beta- and gamma-cyclodextrins to glycogen phosphorylase b: kinetic and crystallographic studies. Protein Sci. 12, 1914-1924. Cover Story {PDB codes: 1P2G, 1P29, 1P2D, 1P2B}

Leonidas, D.D., Chabali, G.B., Chrysina, E.D., Kosmopoulou, M.N., Oikonomakos, N.G., Vlassi, M., Frankling, C. and Acharya, K.R. (2003). High resolution crystal structures of Ribonuclease A complexed with adenylic and uridylic nucleotide inhibitors. Implications for structure-based design of ribonucleolytic inhibitors. Protein Sci. 12, 2559-2574. Cover story {PDB codes: 1O0H, 1O0N, 1O0F, 1O0O}

Kosmopoulou, M.N., Leonidas, D.D., Chrysina, E.D., Bischler, N., Eisenbrand, G., Sakarellos, C.E., Pauptit, R., Oikonomakos, N.G. (2004). Binding of the potential antitumour agent indirubin-5-sulphonate at the inhibitor site of rabbit muscle glycogen phosphorylase b. Eur. J. Biochem. 271, 2280-2290. {PDB codes: 1UZU)

Chrysina, E.D., Kosmopoulou, M.N., Kardakaris, R., Bischler, N., Leonidas, D.D., Kannan, T., Loganathan, T., and Oikonomakos, N.G. (2005) Binding of b-D-glucopyranosyl bismethoxyphosphoramidate to glycogen phosphorylase b. Kinetic and crystallographic studies. Bioorg. Med. Chem. 13, 765-772. {PDB code:1XC7}

Chrysina, E.D., Kosmopoulou, M.N., Tiraidis, C., Kardakaris, R., Bischler, N., Leonidas, D.D., Hadady, Z., Somsak, L., Docsa, T., Gergely, P., and Oikonomakos, N.G. (2005). Kinetic and crystallographic studies on 2-(b-D-glucopyranosyl)-5-methyl-1, 3, 4-oxadiazole, -benzothiazole, and -benzimidazole, inhibitors of muscle glycogen phosphorylase b. Evidence for a new binding site. Protein Sci. 14, 873-888. {PDB codes: 1XL0, 1XL1, 1XKX}

Oikonomakos, N.G., Kosmopoulou, M.N., Chrysina, E.D., Leonidas, D.D., Kostas, I.D., Wendt, K.U., Klabunde, T., and Defossa, E. (2005) Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs. Protein Sci.14, 1760-1771. {PDB codes: 1WUT, 1WVX, 1WV0, 1WV1}

Watson, K.A., Chrysina, E.D., Tsitsanou K.E., Zographos, S.E., Gregoriou, M., Archontis, G., Fleet, G.W.J., and
Oikonomakos, N.G. (2005) Kinetic and crystallographic studies of glucopyranose spirohydantoin and glucopyranosylamine analogues inhibitors of glycogen phosphorylase. Proteins: Structure, Function, and Bioinformatics 61, 966-983. {PDB codes: 1GGN, 1FTQ, 1FTW, 1FTY, 1FU4, 1FU7, 1FU8, 1P4H, 1FS4, 1B4D, 1GG8, 2PRJ}

Archontis, G., Watson, K.A., Xie, Q., Andreou, G., Chrysina, E.D., Zographos, S.E., Oikonomakos, N.G., and Karplus, M. (2005) Molecular recognition and relative binding of glucopyranose spirohydantoin analogues to glycogen phosphorylase: a free energy perturbation study. Proteins: Structure, Function, and Bioinformatics 61. 984-988.

Hatzopoulos, G.N., Leonidas, D.D., Kardakaris, R., Kobe, J., and Oikonomakos, N.G. (2005) The binding of IMP to ribonuclease A. FEBS J. 272, 3988-4001.

Kosmopoulou, M.N., Leonidas, D.D., Chrysina, E.D., Eisenbrand, G., and Oikonomakos, N.G. (2005) Indirubin-3'-aminooxy-acetate inhibits glycogen phosphorylase by binding at the inhibitor and the allosteric site. Broad specificities of the two sites. Letters in Drug Design & Discovery 2, 377-390 {PDB code: 1Z62}

Klabunde, T., Wendt, K.U., Kadereit, D., Brachvogel, V., Burger, H.-J., Herling, A.W., Oikonomakos, N.G., Kosmopoulou, M.N., Schmoll, D., Sarubbi, E., von Roedern, E., Sch?nafinger, K., and Defossa, E. (2005). Acyl Ureas as Human Liver Glycogen Phosphorylase Inhibitors for the Treatment of Type 2 Diabetes. J. Med. Chem. 48, 6178-6193.

Anagnostou, E., Kosmopoulou, M.N., Chrysina, E.D., Leonidas, D.D., Hadjiloi, T., Tiraidis, C., Zographos, S.E., Gyorgydeak, Z., Somsak, L., Docsa, T., Gergely, P., and Oikonomakos, N.G. (2006) Crystallographic studies on two bioisosteric analogues, N-acetyl-b-D-glucopyranosylamine and N-trifluoracetyl-b-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase. Bioorg. Med. Chem. 14, 181-189. Cover illustration.

Lukacs, C.M., Oikonomakos, N.G., Crowther, R.L., Hong, L.-N., Kammlott, R.U., Levin, W., Li, S., Liu, C.-M., Lucas-McGady, D., Reik, L., and Pietranico, S. (2006). The crystal structure of human muscle glycogen phosphorylase a with bound glucose and AMP: an intermediate conformation with T-state and R-state features. Proteins 63, 1123-1126.

Hadjiloi, T., Tiraidis, C., Chrysina, E.D., Leonidas, D.D., Oikonomakos, N.G., Tsipos, P. and Gimisis, T. (2006). Binding of oxalyl derivatives of b-D-glucopyranosylamine to muscle glycogen phosphorylase b. Bioorg. Med. Chem. 14, 3872-3882. Cover illustration

Petsalakis, E.I., Chrysina, E.D., Tiraidis, C., Hadjiloi, T., Leonidas, D.D., Oikonomakos, N.G., Aich, U., Varghese, B. and Loganathan, D. (2006). Crystallographic studies on N-azidoacetyl-b-D-glucopyranosylamine, an inhibitor of glycogen phosphorylase: comparison with N-acetyl-b-D-glucopyranosylamine. Bioorg. Med. Chem. 14, 5316-5324.

He, L., Zang, Y.Z., Tanoh, M., Chen, G.-R., Praly, J.-P., Chrysina, E.D., Tiraidis, C., Kosmopoulou, M.N., Leonidas, D.D. and Oikonomakos, N.G. (2006). Synthesis of C-D-glycopyranosyl-hydroquinones and -benzoquinones. Inhibition of and binding to glycogen phosphorylase in the crystal. Eur. J. Org. Chem., in press.

Whittamore, P.R.O., Addie, M.S., Bennett, S.N.L., Birch, A.M., Butters, M., Godfrey, L., Kenny, P.W., Morley, A.D., Murray, P.M., Oikonomakos, N.G., Otterbein, L.R., Pannifer, A.D., Parker, J.S., Readman, K., Siedlecki, P.S., Schofield, P., Stocker, A., Taylor, M.J., Townsend, L.A., Whalley, D.P., and Whitehouse, J. (2006). Novel thienopyrrole glycogen phosphorylase inhibitors: synthesis, in vitro SAR and crystallographic studies. Bioorg. Med. Chem. Lett. 16, 5567-5571.

Leonidas, D.D., Maiti, T.K., Samanta, A., Dasgupta, S., Pathak, T., Zographos, S.E., and Oikonomakos, N.G. (2006). The binding of 3/-N-piperidine-4-carboxyl-3/-deoxy-ara-uridine to ribonuclease A in the crystal. Bioorg. Med. Chem. 14, 6055-6064.

Oikonomakos, N.G., Tiraidis, C., Leonidas, D.D., Zographos, S.E., Kristiansen, M., Jessen, C.U., Norskov-Lauritsen, L., and Agius, L. (2006). Iminosugars as potential inhibitors of glycogenolysis: structural insights into the molecular basis of glycogen phosphorylase inhibition. J. Med. Chem. 49, 5687-5701.

Birch, A.M., Kenny, P.W., Oikonomakos, N.G., Otterbein, L.R., Schofield, P., Whittamore, P.R.O., and Whalley, D.P. (2006). Development of potent, orally active 1-substituted-3,4-dihydro-2-quinolone glycogen phosphorylase inhibitors. Bioorg. Med. Chem. Lett., 17, 394-399.

Hampson, L.J., Arden, C., Agius, L., Ganotidis, M., Kosmopoulou, M.N., Tiraidis, C., Elemes, Y., Sakarellos, C., Leonidas, D.D., and Oikonomakos, N.G. (2006). Regulation of hepatic glycogen metabolism by purine nucleoside site inhibitors of glycogen phosphorylase. Bioorg. Med. Chem. 14, 7835-7845

Polydoridis, S., Leonidas, D.D., Oikonomakos, N.G., and Archontis, G.A. (2007).Recognition of Ribonuclease A by 3 '-5'-Pyrophosphate-linked Dinucleotide Inhibitors: a Molecular Dynamics/Continuum Electrostatics Analysis. Biophys. J. 92, 1659-1672

He, L., Zang, Y.Z., Tanoh, M., Chen, G.-R., Praly, J.-P.,Chrysina, E.D., Kosmopoulou, M.N., Leonidas, D.D., and Oikonomakos, N.G. (2007).In the Search of Glycogen Phosphorylase Inhibitors: Synthesis of C-D-Glycopyranosyl-benzo(hydro) quinones. Inhibition of and binding to glycogen phosphorylase in the crystal. Eur. J. Org. Chem. 596-606.

Leonidas, D.D., Swamy, B.M., Hatzopoulos, G.N., Gonchigar, S.J., Chachadi, V.B., Inamdar, S.R., Zographos, S.E., and Oikonomakos, N.G.(2007).Structural basis of the carbohydrate recognition of the Sclerotium rolfsii lectin. J. Mol. Biol. 368, 1145-1161

Pantelidou, M., Zographos, S.E., Lederer, C.W., Kyriakides, T., Pfaffl, M.W., and Santama, N. (2007).Differential expression of molecular motors in the motor cortex of sporadic ALS. Neurobiol. Dis. 26, 577-589