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Protein-DNA Interactions - Konstantinos Tripsianes

Research Group Leader
Researcher ID
Phone: +420 54949 6607
E-mail:
Office:

Research areas

  • Structural biology of protein-DNA complexes
  • Small molecule inhibitors
  • NMR structure determination of large proteins

Main objectives

  • Biochemical and structural characterization of protein-DNA interactions involved in DNA repair and transcription
  • Design and pre-clinical evaluation of compounds for lead optimization
  • Development of integrated structural approaches for studying large biomolecules in solution

Content of research

We use NMR and hybrid structural methods, as well as biophysical techniques, to study protein-DNA complexes involved in DNA repair and transcription. Both topics involve proteins that are promising targets for anti-cancer drugs. Therefore the group has a strong interest in structure-based drug design.

Protein-DNA transactions are essential for genome maintenance. We use structural, biochemical, and computational tools to study the function of DNA-repair factors. We employ a combination of solution techniques (NMR, SAXS-SANS, FRET) to structurally characterize protein-DNA complexes and understand dynamic rearrangements induced upon DNA binding. Structural findings are complemented in a broader functional context by genetic, molecular or cell biology, and single-molecule assays (L. Krejci, Masaryk University).

DNA repair as a therapeutic target has received considerable attention owing to the promise of drugs that target DNA-repair enzymes and potentiate conventional cytotoxic therapy through mechanism-based approaches. In this direction, we study the binding of small molecules to protein targets of interest, in order to modulate their function for potential therapeutic benefit. Promising inhibitors are identified based on in silico design (Prof. E. Mikros, University of Athens; Prof. J. Tuszynski, University of Alberta) or high-throughput screening (P. Bartunek, IMG Prague).

kostas

list / cards

Name and position

E-mail

Phone

Konstantinos Tripsianes, Ph.D.
Research Group Leader
+420 54949 6607
Thomas Evangelidis
Postdoctoral Fellow
+420 54949 7834
Anna Papageorgiou
PhD Student
+420 54949 7834
Vlastimil Tichý
Postdoc
Monika Kubíčková
technička
Jitender Kumar
odborný pracovník

SELECTED PUBLICATIONS

2017

  • DAWIDOWSKI, M; EMMANOUILIDIS, L; KALEL, V C; TRIPSIANES, K; SCHORPP, K; HADIAN, K; KAISER, M; MÄSER, P; KOLONKO, M; TANGHE, S; RODRIGUEZ, A; SCHLIEBS, W;. ERDMANN, R; SATTLER, M; POPOWICZ, G M, 2017:Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites. SCIENCE 355 (6332), p. 1416 - 1420.
  • EMMANOUILIDIS, L; SCHUTZ, U; TRIPSIANES, K; MADL, T; RADKE, J; RUCKTASCHEL, R; WILMANNS, M; SCHLIEBS, W; ERDMANN, R; SATTLER, M, 2017:Allosteric modulation of peroxisomal membrane protein recognition by farnesylation of the peroxisomal import receptor PEX19. Nature communications 8 (13)
  • PEKARIK, V; PESKOVA, M; GURAN, R; NOVACEK, J; HEGER, Z; TRIPSIANES, K; KUMAR, J; ADAM, V, 2017:Visualization of stable ferritin complexes with palladium, rhodium and iridium nanoparticles detected by their catalytic activity in native polyacrylamide gels. DALTON TRANSACTIONS 46 (40), p. 13690 - 13694.
  • SUPEKAR, S; PAPAGEORGIOU, AC; GEMMECKER, G; PELTZER, R; JOHANSSON, MP; TRIPSIANES, K; SATTLER, M;KAILA VRK, 2017:Conformational Selection of Dimethylarginine Recognition by the Survival of Motor Neuron Tudor Domain. ANGEWANDTE CHEMIE

2015

  • CAMARGO, DCR; TRIPSIANES, K; KAPP, TG; MENDES, J; SCHUBERT, J; CORDES, B; REIF, B, 2015:Cloning, expression and purification of the human Islet Amyloid Polypeptide (hIAPP) from Escherichia coli. PROTEIN EXPRESSION AND PURIFICATION 106 , p. 49 - 56.

2014

  • TRIPSIANES, K; FRIBERG, A; BARRANDON, C; BROOKS, M; VAN TILBEURGH, H; SERAPHIN, B; SATTLER, M, 2014:A Novel Protein-Protein Interaction in the RES (REtention and Splicing) Complex. JOURNAL OF BIOLOGICAL CHEMISTRY 289 (41), p. 28640 - 28650.
  • TRIPSIANES, K; CHU, NK; FRIBERG, A; SATTLER, M; BECKER, CFW, 2014:Studying Weak and Dynamic Interactions of Posttranslationally Modified Proteins using Expressed Protein Ligation. ACS CHEMICAL BIOLOGY 9 (2), p. 347 - 352.
  • ZHANG, ZY; PORTER, J; TRIPSIANES, K; LANGE, OF, 2014:Robust and highly accurate automatic NOESY assignment and structure determination with Rosetta. JOURNAL OF BIOMOLECULAR NMR 59 (3), p. 135 - 145.

2011

  • TRIPSIANES, K; MADL, T; MACHYNA, M; FESSAS, D; ENGLBRECHT, C; FISCHER, U; NEUGEBAUER, KM; SATTLER, M, 2011:Structural basis for dimethylarginine recognition by the Tudor domains of human SMN and SPF30 proteins. NATURE STRUCTURAL & MOLECULAR BIOLOGY 18 (12), p. 1414 - U136.

1. Development and evaluation of next-generation drug design algorithms

Supervisor: Konstantinos Tripsianes, Ph.D.
Consultants: doc. RNDr. Tomáš Brázdil, Ph.D., Thomas Evangelidis, M.Phil., Ph.D.

Annotation:

Hit compounds from virtual screening are chemically modified to increase their binding affinity against a protein receptor. To be able to select potent analogs among hundreds of candidates, a new algorithm named ScaffOpt has been developed. Scaffopt employs multiple machine learning techniques to create, on the fly, a receptor specific Metapredictor, which ctripsianombines the predictions of an ensemble of artificial neural networks to predict the relative binding affinity of each synthetic compound with great accuracy. The aim of the project is to extend ScaffOpt algorithm to do virtual screening on large chemical databases either by ligand similarity or docking, or combination thereof. The performance of the new algorithms will be evaluated retrospectively on available datasets or by application to real drug design endeavors conducted in concert with collaborating laboratories. The successful candidate should have strong interest to modern structure- and ligand-based drug design, and the appropriate computational background to gain expertise in machine learning algorithms, Python programming, chemoinformatics tools, and molecular dynamics simulations.

Keywords: ScaffOpt, Metapredictor, binding affinity, virtual screening, ligand-based drug design, docking, Python programming, next-generation drug design, next-generation drug

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