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The structural biology of today is the pharmacology, therapy, and biotechnology of tomorrow

A gateway to realm of structural data for biochemists, biophysicists, molecular biologist, and all scientists whose research benefits from accurate structure determination of biological macromolecules, assemblies, and complex molecular machineries at atomic resolution.

Open access to 10 high-end core facilities and assisted expertise in NMR, X-ray crystallography and crystallization, cryo-electron microscopy and tomography, biophysical characterization of biomolecular interaction, nanobiotechnology, proteomics and structural mass spectrometry.

A distributed infrastructure constituted by Core Facilities of CEITEC (Central European Institute of Technology), located in Brno, and BIOCEV (Biotechnology and Biomedicine Centre), located in Vestec near Prague, Central Bohemia.

CIISB Research Results

L.D. Chakkarapani, et al.: Selective and sensitive determination of phenolic compounds using carbon screen printing electrodes modified with reduced graphene oxide and silver nanoparticles, Appl. Mater. Today, 37 (2024) 14, 10.1016/j.apmt.2024.102113

P. Janovsky, et al.: para-Phenylenediamine Dimer as a Redox-Active Guest for Supramolecular Systems, Chemistry-a European Journal, 30 (2024) 12, 10.1002/chem.202400535

V. Kundrat, et al.: WS2 fullerene/plate nanofibers: The tunable crossroad between dimensionalities, Ceram. Int., 50 (2024) 7314-7322, 10.1016/j.ceramint.2023.11.345

J.M. Mierzwicka, et al.: Engineering PD-1-targeted small protein variants for in vitro diagnostics and in vivo PET imaging, J. Transl. Med., 22 (2024) 19, 10.1186/s12967-024-05210-x

M. Morici, et al.: RAPP-containing arrest peptides induce translational stalling by short circuiting the ribosomal peptidyltransferase activity, Nature Communications, 15 (2024) 16, 10.1038/s41467-024-46761-3

P. Pourali, et al.: Accumulation and toxicity of biologically produced gold nanoparticles in different types of specialized mammalian cells, Biotechnol. Appl. Biochem., (2024) 13, 10.1002/bab.2575

J. Sabo, et al.: CKAP5 enables formation of persistent actin bundles templated by dynamically instable microtubules, Current Biology, 34 (2024) 21, 10.1016/j.cub.2023.11.031

D. Svestka, et al.: Asymmetric Organocatalyzed Transfer Hydroxymethylation of Isoindolinones Using Formaldehyde Surrogates, Organic Letters, 26 (2024) 2505-2510, 10.1021/acs.orglett.4c00818

More publications

CIISB Research Highlights

the best of science obtained using CIISB Core Facilities

  • Angewandte Chemie Int. Ed. 2024

    Angewandte Chemie Int. Ed. 2024

    A tetrastranded DNA structure, KNa-quadruplex (KNaQ), is described. KNaQ forms from repetitive DNA sequences that are abundant in (parasitic) worms but extremely rare in humans or livestock. This opens a possibility of exploiting the fold as a plausible antiparasitic drug target. The structure's unique properties distinguish it from all other known DNA quadruplexes and can be used to design novel recognition DNA elements/sensors.

    Lukáš Trantírek and Martina Zivkovič Research Groups

    Significance

    DNA quadruplex structures provide an additional layer of regulatory control in genome maintenance and gene expression and are widely used in nanotechnology. We report the discovery of an unprecedented tetrastranded structure formed from a native G-rich DNA sequence originating from the telomeric region of Caenorhabditis elegans. The structure is defined by multiple properties that distinguish it from all other known DNA quadruplexes. Most notably, the formation of a stable so-called KNa-quadruplex (KNaQ) requires concurrent coordination of K+ and Na+ ions at two distinct binding sites. This structure provides novel insight into G-rich DNA folding under ionic conditions relevant to eukaryotic cell physiology and the structural evolution of telomeric DNA. It highlights the differences between the structural organization of human and nematode telomeric DNA, which should be considered when using C. elegans as a model in telomere biology, particularly in drug screening applications. Additionally, the absence/presence of KNaQ motifs in the host/parasite introduces an intriguing possibility of exploiting the KNaQ fold as a plausible antiparasitic drug target. The structure's unique shape and ion dependency and the possibility of controlling its folding by using low-molecular-weight ligands can be used for the design or discovery of novel recognition DNA elements and sensors.

    Gajarsky, M. et al. DNA Quadruplex Structure with a Unique Cation Dependency,

    Angew. Chem. Int. Ed. 2024, e202318261. https://doi.org/10.1002/anie.202313226

  • Nature Communications 2024

    Nature Communications 2024

    Slice through a tomogram of a stage-III ΔspoIVB B. subtilis sporangium, used for the segmentation (ii) of various forespore and mother cell ultrastructures. Panel ii shows the corresponding segmentation.

    Christine Moriscot and Cecile Morlot Research Groups

    Significance

    Bacterial spores owe their incredible resistance capacities to molecular structures that protect the cell content from external aggressions. Among the determinants of resistance are the quaternary structure of the chromosome and an extracellular shell made of proteinaceous layers (the coat), the assembly of which remains poorly understood. Here, in situ cryo-electron tomography on lamellae generated by cryo-focused ion beam micromachining provides insights into the ultrastructural organization of Bacillus subtilissporangia. The reconstructed tomograms reveal that early during sporulation, the chromosome in the forespore adopts a toroidal structure harboring 5.5-nm thick fibers. At the same stage, coat proteins at the surface of the forespore form a stack of amorphous or structured layers with distinct electron density, dimensions and organization. By analyzing mutant strains using cryo-electron tomography and transmission electron microscopy on resin sections, we distinguish seven nascent coat regions with different molecular properties, and propose a model for the contribution of coat morphogenetic proteins.

    Bauda, E., Gallet, B., Moravcova, J. et al. Ultrastructure of macromolecular assemblies contributing to bacterial spore resistance revealed by in situ cryo-electron tomography.

    Nat Commun 15, 1376 (2024). https://doi.org/10.1038/s41467-024-45770-6

  • Nature 2024

    Nature 2024

    Model for ameloblast-specific autoantibody production in patients with coeliac disease.

    Jakub Abramson Research Group

    Significance

    Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation—amelogenesis. Amelogenesis depends on multiple ameloblast-derived proteins that function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins results in a group of rare congenital disorders called amelogenesis imperfecta. Defects in enamel formation are also found in patients with autoimmune polyglandular syndroze type-1 (APS-1), caused by AIRE deficiency, and in patients diagnosed with coeliac disease. However, the underlying mechanisms remain unclear. Here we show that the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. This in turn results in a breakdown of central tolerance, and subsequent generation of corresponding autoantibodies that interfere with enamel formation. However, in coeliac disease, the generation of such autoantibodies seems to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel tissue. Both conditions are examples of a previously unidentified type of IgA-dependent autoimmune disorder that we collectively name autoimmune amelogenesis imperfecta.

    Gruper, Y., Wolff, A.S.B., Glanz, L. et al. Autoimmune amelogenesis imperfecta in patients with APS-1 and coeliac disease.

    Nature 624, 653–662 (2023). https://doi.org/10.1038/s41586-023-06776-0

More publications Research Highlights archive

Reader’s Corner

literature to read, science to follow

In this section, a distinct selection of six highly stimulating research publications and reviews published during past 6 months is presented. It is our hope that links to exciting science, which deserves attention of the structural biology community, will help you to locate gems in the steadily expanding jungle of scientific literature. You are welcome to point out to any paper you found interesting by sending a link or citation to readerscorner@ciisb.org. The section is being updated regularly.


 

7 Dec 2023

Celebrating 30 years of Structure

Journal Structure was launched in 1993 as the first journal exclusively dedicated to structural biology by our founding academic chief editors, Wayne A. Hendrickson and Carl-Ivar Br€ande´ n, who were later joined by Alan Fersht. Christopher Lima and Andrej Sali became academic chief editors of Structure in 2003, and they were at the helm of the journal for 18 years until stepping down in the autumn 2021.

Structure is now celebrating its 30th birthday with this special anniversary issue. Editors commissioned reviews to highlight recent developments in different areas of structural biology. Sabine Botha and Petra Fromme provide an overview of the current state of serial femtosecond crystallography (SFX) research, the impact COVID-19 had on the SFX community, and how scientists adapted to these challenges. Koji Yonekura and his co-workers describe their contributions toward the development of electron 3D crystallography/microcrystal electron diffraction (MicroED) and highlight applications and current limitations of this method. Vaibhav KumarShukla, Gabriella Heller, and Flemming Hansen discuss the impact of artificial intelligence (AI) on biomolecular nuclear magnetic resonance (NMR) spectroscopy. Tuo Wang and his colleagues report how solid-state NMR is used to study the structures of fungaland plant cell walls. Syma Khalid and her co-workers define the term ‘‘computational microbiology’’ and describe state-of-the-art molecular dynamics imulations of bacterial systems.

21 Nov 2023

Intrinsic structural dynamics dictate enzymatic activity and inhibition (PNAS)

Enzymes are known to sample various conformations, many of which are critical for their biological function. However, structural characterizations of enzymes predominantly focus on the most populated conformation. As a result, single-point mutations often produce structures that are similar or essentially identical to those of the wild-type enzyme despite large changes in enzymatic activity. Here, we show for mutants of a histone deacetylase enzyme (HDAC8) that reduced enzymatic activities, reduced inhibitor affinities, and reduced residence times are all captured by the rate constants between intrinsically sampled conformations that, in turn, can be obtained independently by solution NMR spectroscopy. Thus, for the HDAC8 enzyme, the dynamic sampling of conformations dictates both enzymatic activity and inhibitor potency. Our analysis also dissects the functional role of the conformations sampled, where specific conformations distinct from those in available structures are responsible for substrate and inhibitor binding, catalysis, and product dissociation. Precise structures alone often do not adequately explain the effect of missense mutations on enzymatic activity and drug potency. Our findings not only assign functional roles to several conformational states of HDAC8 but they also underscore the paramount role of dynamics, which will have general implications for characterizing missense mutations and designing inhibitors.

Reader’s Corner Archive

Quote of July

“Medicine is a science of uncertainty and an art of probability.”

William Osler

https://ec.europa.eu/info/research-and-innovation/research-area/health-research-and-innovation/coronavirus-research-and-innovation/covid-research-manifesto_en

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