Protein Structure and Dynamics - Lukáš Žídek
CEITEC MU CEITEC MU
Protein Structure and Dynamics - Lukáš Žídek

PhD Topics

1.     Structural characterization of hybrid proteins involved in neurodegenerative diseases

Supervisor: Jozef Hritz, Ph.D.                                    

Annotation:

The hybrid proteins contains both structured and disordered regions of considerable lengths. Disordered region is often involved in the regulation of their enzymatic activity. The aim of this PhD project will be structural characterization of disordered region within the selected hybrid proteins having medicinal relevance. The structural properties will be studied by combination of solution NMR spectroscopy and computational simulations. Finally, the impact of phosphorylation on the interaction with client proteins will be evaluated by biophysical interaction techniques.

Recommended literature:

Zapletal, V.; Mládek, A.; Melková, K.; Louša, P.; Nomilner, E.; Jaseňáková, Z.; Kubáň, V.; Makovická, M.; Laníková, A.; Žídek L.; Hritz, J. Choice of force field for proteins containing structured and intrinsically disordered regions. Biophys. J. 2020, 118, 1621 – 1633

Přecechtělová, J.; Mládek, A.; Zapletal, V.; Hritz, J.: Quantum Chemical Calculations of NMR Chemical Shifts in Phosphorylated Intrinsically Disordered Proteins, JCTC 2019, 15, 5642-5658.

Nagy, G., Oostenbrink, C., and Hritz, J. Exploring the binding pathways of the 14-3-3ζ protein: Structural and free-energy profiles revealed by Hamiltonian replica exchange molecular dynamics with distancefield distance restraints. PLoS One 2017, 12, 1–30.

Hritz J.; Byeon I-J.; Krzysiak T.; Martinez A.; Sklenář V.; Gronenborn A.M. Dissection of binding between a phosphorylated tyrosine hydroxylase peptide and 14-3-3ζ: a complex story elucidated by NMR. Biophys. J. 2014, 107, 2185-2194

Louša, P.; Nedozrálová, H.; Župa, E.; Nováček, J.; Hritz, J.:  Phosphorylation of the regulatory domain of human tyrosine hydroxylase 1 monitored using non-uniformly sampled NMR. Biophysical Chemistry 2017, 223, 25-29

Keywords: hydrid proteins, disordered region, NMR spectroscopy, neurodegenerative diseases phosphorylation, computational simulations

 

2.     Structural properties of human carbonic anhydrase IX and design of its inhibitors

Supervisor: Jozef Hritz, Ph.D.

Annotation:

Carbonic anhydrase (CA) IX is cellular surface protein that in contrast to another isoforms in healthy condition is present mostly in gastrointestinal tract.  However, it is highly upregulated in the cancer cells adapting to the extracellular environment while maintaining physiological conditions inside the cancer cell. The main aim of this PhD project is to characterize structural changes of CA-IX reflecting pH changes by NMR spectroscopy. It will also involve a computational design of inhibitors of CA-IX. Finally, their binding affinity will be experimentally verified by biophysical interaction methods. 

Recommended literature:

Pastorekova S, Parkkila S, Parkkila AK, et al. Carbonic anhydrase IX, MN/CA IX: Analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts. Gastroenterology 1997; 112: 398-408

Supuran CT; Scozzafava A. (2000) Carbonic anhydrase inhibitors and their therapeutic potential. Expert Opinion on Therapeutic Patents. 10 (5): 575–600

Alterio, V., Di Fiore, A., De Simone, G. (2009) Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX Proc Natl Acad Sci U S A 106: 16233-16238

Zapletal, V.; Mládek, A.; Melková, K.; Louša, P.; Nomilner, E.; Jaseňáková, Z.; Kubáň, V.; Makovická, M.; Laníková, A.; Žídek L.; Hritz, J. Choice of force field for proteins containing structured and intrinsically disordered regions. Biophys. J. 2020, 118, 1621 – 1633

Nagy, G.; Oostenbrink, C.; Hritz, J. (2017) Exploring the Binding Pathways of the 14-3-3z Protein: Structural and Free-Energy Profiles Revealed by Hamiltonian Replica Exchange Molecular Dynamics with Distance Field Distance Restraints. PLoS ONE,12(7), e0180633

Keywords: carbonic anhydrase, cancer, intrinsically disordered region, NMR, inhibitor