Wiktor Koźmiński's NMR group

Biological and Chemical Research Centre, University of Warsaw

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Wiktor Koźmiński's NMR Group

Open Positions


Project: New tools and applications of NMR spectroscopy beyond resolution limitation.

Project coordinator: prof. Wiktor Koźmiński.
Project duration: 2016 - 2021.


Positions for MSc students available.


The aim of the project is an expansion of capabilities of the high-resolution nuclear magnetic resonance (NMR) spectroscopy which is a fundamental tool of modern structural biology. The structure and dynamics of proteins will be studied using new spectral parameters, such as cross-correlated relaxation rates. The research conducted in the frames of the project will make use of multidimensional NMR spectroscopy of isotopically enriched samples (13C, 15N, 2H) of proteins, both of folded and disordered nature. In addition, high hydrostatic pressure NMR will be employed to study conformational equilibria and dynamics of investigated proteins. Exceptionally high-resolution of 4 and 5 dimensional spectra will be achieved thanks to non-uniform sampling and advanced processing tools.

Candidate for MSc position shoud hold BSc preferably in chemistry, physics, biology or computer-science. All stipends are funded from NCN MAESTRO grant.

More info: prof. Wiktor Koźmiński, This e-mail address is being protected from spambots. You need JavaScript enabled to view it
Application deadline: ongoing recruitment.


New Article in Journal of Biomolecular NMR


A novel high-dimensional NMR experiment for resolving protein backbone dihedral angle ambiguities

Clemens Kauffmann, Krzysztof Kazimierczuk, Thomas C. Schwarz, Robert Konrat, Anna Zawadzka-Kazimierczuk

CCR Ania

Intrinsically disordered proteins (IDPs) are challenging established structural biology perception and urge a reassessment of the conventional understanding of the subtle interplay between protein structure and dynamics. Due to their importance in eukaryotic life and central role in protein interaction networks, IDP research is a fascinating and highly relevant research area in which NMR spectroscopy is destined to be a key player. The flexible nature of IDPs, as a result of the sampling of a vast conformational space, however, poses a tremendous scientific challenge, both technically and theoretically. Pronounced signal averaging results in narrow signal dispersion and requires higher dimensionality NMR techniques. Moreover, a fundamental problem in the structural characterization of IDPs is the definition of the conformational ensemble sampled by the polypeptide chain in solution, where often the interpretation relies on the concept of ‘residual structure’ or ‘conformational preference’. An important source of structural information is information-rich NMR experiments that probe protein backbone dihedral angles in a unique manner. Cross-correlated relaxation experiments have proven to fulfil this task as they provide unique information about protein backbones, particularly in IDPs. Here we present a novel cross-correlation experiment that utilizes non-uniform sampling detection schemes to resolve protein backbone dihedral ambiguities in IDPs. The sensitivity of this novel technique is illustrated with an application to the prototypical IDP α-Synculein for which unexpected deviations from random-coil-like behaviour could be observed.


New Article in Journal of the American Chemical Society


Automated Backbone NMR Resonance Assignment of Large Proteins Using Redundant Linking from a Single Simultaneous Acquisition

Jan Stanek, Tobias Schubeis, Piotr Paluch, Peter Günter, Loren B. Andreas, Guido Pintacuda

ja0c00251 0006

Thanks to magic-angle spinning (MAS) probes with frequencies of 60–100 kHz, the benefit of high-sensitivity 1H detection can now be broadly realized in biomolecular solid-state NMR for the analysis of microcrystalline, sedimented, or lipid-embedded preparations. Nonetheless, performing the assignment of all resonances remains a rate-limiting step in protein structural studies, and even the latest optimized protocols fail to perform this step when the protein size exceeds ∼20 kDa. Here, we leverage the benefits of fast (100 kHz) MAS and high (800 MHz) magnetic fields to design an approach that lifts this limitation. Through the creation, conservation, and acquisition of independent magnetization pathways within a single triple-resonance MAS NMR experiment, a single self-consistent data set can be acquired, providing enhanced sensitivity, reduced vulnerability to machine or sample instabilities, and highly redundant linking that supports fully automated peak picking and resonance assignment. The method, dubbed RAVASSA (redundant assignment via a single simultaneous acquisition), is demonstrated with the assignment of the largest protein to date in the solid state, the 42.5 kDa maltose binding protein, using a single fully protonated microcrystalline sample and 1 week of spectrometer time.


New Article in Angewandte Chemie


Protein NMR resonance assignment without spectral analysis: 5D SOlid‐state Automated Projection SpectroscopY (SO‐APSY)

Henry W. Orton, Jan Stanek, Tobias Schubeis, Dylan Foucaudeau, Claire Ollier, Adrian W. Draney, Tanguy Le Marchand, Diane Cala-De Paepe, Isabella C. Felli, Roberta Pierattelli, Sebastian Hiller, Wolfgang Bermel, Guido Pintacuda


Narrow proton signals, high sensitivity, and efficient coherence transfersprovided by fast magic-angle spinning at high magnetic fields make automated projection spectroscopy feasible in protein solid-state NMR. We present the first ultra-high dimensional implementation of this approach where 5D peak lists are reconstructed from a number of 2D projections for protein samples of different molecular size and aggregation state, featuring limited dispersion of chemical shifts or inhomogeneous broadenings. The resulting datasets are particularly suitable to automated analysis, yielding rapid and unbiased backbone resonance assignments.


New Article in ACS Medicinal Chemistry Letters


Novel Cyclic Biphalin Analogues by Ruthenium-Catalyzed Ring Closing Metathesis: in Vivo and in Vitro Biological Profile

Azzurra Stefanucci, Wei Lei, Stefano Pieretti, Marilisa Pia Dimmito, Grazia Luisi, Ettore Novellino, Michał Nowakowski, Wiktor Koźmiński, Sako Mirzaie, Gokhan Zengin, John M. Streicher, and Adriano Mollica

ml 2018 00495v 0005

In this work we report the application of the ring-closing metathesis (RCM) to the preparation of two cyclic olefin-bridged analogues of biphalin (Tyr-d-Ala-Gly-Phe-NH-NH ← Phe ← Gly ← d-Ala ← Tyr), using the second generation Grubbs’ catalyst. The resulting cis- and trans-cyclic isomers were identified, fully characterized, and tested in vitro at μ (ΜΟR), δ (DOR), and κ (KOR) opioid receptors and in vivo for antinociceptive activity. Both were shown to be full agonists at MOR and potential partial antagonists at DOR, with low potency KOR agonism. They also share a strong antinociceptive effect after intracerebroventricular (i.c.v.) and intravenous (i.v.) administration, higher than that of the cyclic biphalin analogues containing a disulfide bridge between the side chains of two d-Cys or d-Pen residues, previously described by our group.


New Article in Chemistry — A European Journal


Metal exchange in interprotein Zn(II)‐binding site of Rad50 hook domain – structural insights into Cd(II)‐induced DNA repair inhibition

Michał Padjasek, Maciej Maciejczyk, Michał Nowakowski, Olga Kerber, Maciej Pyrka, Wiktor Koźmiński, Artur Krężel


Cd(II) is a major genotoxic agent that readily displaces Zn(II) in a multitude of zinc proteins, abrogates redox homeostasis and deregulates cellular metalloproteome. To date this displacement has been described mostly for cysteine‐rich intraprotein binding sites in certain zinc finger domains and metallothionein. To visualize how Zn(II) to Cd(II) swap can affect the target protein’s status and thus understand the molecular basis of Cd(II)‐induced genotoxicity we focused on an intermolecular Zn(II)‐binding site from the crucial DNA repair protein Rad50 and its zinc hook domain. Using a length‐varied peptide base we hereby demonstrate that Zn(II) to Cd(II) displacement in Rad50’s hook domain alters it in a bimodal fashion: (i) Cd(II) induces around a two‐orders‐of‐magnitude stabilization effect (log K 12 Zn(II) = 20.8 vs log K 12 Cd(II) = 22.7), which defines an extremely high affinity of a peptide towards a metal ion, and (ii) disrupts the overall assembly of the domain, as shown by NMR and anisotropy decay data. Based on our results we propose a novel model explaining the molecular mechanism of Cd(II) genotoxicity that underlines Cd(II)’s impact on Rad50’s dimer stability and quaternary structure that could potentially result in abrogation of the major DNA damage response pathway.


New Review in Journal of Inorganic Biochemistry


Towards the functional high-resolution coordination chemistry of blood plasma human serum albumin

Samah Al-Harthi, Joanna Lachowicz, Michał Nowakowski, Mariusz Jaremko, Łukasz Jaremko

1 s2.0 S0162013419301734 ga1 lrg

Human serum albumin (HSA) is a monomeric, globular, multi-carrier and the most abundant protein in the blood. HSA displays multiple ligand binding sites with extraordinary binding capacity for a wide range of ions and molecules. For decades, HSA's ability to bind to various ligands has led many scientists to study its physiological properties and protein structure; indeed, a better understanding of HSA-ligand interactions in human blood, at the atomic level, will likely foster the development of more potent, and overall more performant, diagnostic and therapeutic tools against serious human disorders such as diabetes, cardiovascular disorders, and cancer. Here, we present a concise overview of the current knowledge of HSA's structural characteristics, and its coordination chemistry with transition metal ions, within the scope and limitations of current techniques and biophysical methods to reach atomic resolution in solution and in blood serum. We also highlight the overwhelming need of a detailed atomistic understanding of HSA dynamic structures and interactions that are transient, weak, multi-site and multi-step, and allosterically affected by each other. Considering the fact that HSA is a current clinical tool for drug delivery systems and a potential contender as molecular cargo and nano-vehicle used in biophysical, clinical and industrial fields, we underline the emerging need for novel approaches to target the dynamic functional coordination chemistry of the human blood serum albumin in solution, at the atomic level.


New Article in Physical Chemistry Chemical Physics


Shape Adaptation of Quinine in Cyclodextrin Cavities: NMR studies

Jacek Wójcik, Andrzej Ejchart, Michał Nowakowski


Complex formation between quinine and natural cyclodextrins (CD) was studied using NMR spectroscopy. The strongest association was observed for complexes of neutral quinine molecule with βCD. Association constants for monokationic quinine were one order of magnitude smaller, while dikationic quinine did not bind to CDs. Distribution of complexation-induced shifts and ROESY spectra revealed bimodal quinine binding in complexes built up by βCD and γCD. Complex formation resulted in decrease of vicinal coupling constant between H2 and H9 protons owing to the rotation about C2–C9 bond and in consequence in mutual reorientation of two main constituents of quinine: quinoline and quinuclidine. DFT calculations allowed to establish that H2 and H9 protons are antiperiplanar in the prevailing quinine conformer(s) in aqueous solution. Conformers with synclinal H2, H9 protons become to participate in quinine complexed with CDs.

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