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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

Y. Luo, et al.: A sodium/potassium switch for G4-prone G/C-rich sequences, Nucleic Acids Res., 52 (2024) 448-461, 10.1093/nar/gkad1073

M. Soltysová, et al.: Structural characterization of two prototypical repressors of SorC family reveals tetrameric assemblies on DNA and mechanism of function, Nucleic Acids Res., 52 (2024) 7305-7320, 10.1093/nar/gkae434

D. Jankovská, et al.: Anticholinesterase Activity of Methanolic Extract of Amorpha fruticosa Flowers and Isolation of Rotenoids and Putrescine and Spermidine Derivatives, Plants-Basel, 13 (2024) 10, 10.3390/plants13091181

M. Anastasina, et al.: The structure of immature tick-borne encephalitis virus supports the collapse model of flavivirus maturation, Sci. Adv., 10 (2024) 13, 10.1126/sciadv.adl1888

P. Lapcik, et al.: A hybrid DDA/DIA-PASEF based assay library for a deep proteotyping of triple-negative breast cancer, Sci. Data, 11 (2024) 7, 10.1038/s41597-024-03632-2

N. Kunová, et al.: Polyphosphate and tyrosine phosphorylation in the N-terminal domain of the human mitochondrial Lon protease disrupts its functions, Sci Rep, 14 (2024) 17, 10.1038/s41598-024-60030-9

J. Sistkova, et al.: Insight into antibacterial effect of titanium nanotubular surfaces with focus on Staphylococcus aureus and Pseudomonas aeruginosa, Sci Rep, 14 (2024) 20, 10.1038/s41598-024-68266-1

F. Niro, et al.: Fibrotic extracellular matrix impacts cardiomyocyte phenotype and function in an iPSC-derived isogenic model of cardiac fibrosis, Transl. Res., 273 (2024) 58-77, 10.1016/j.trsl.2024.07.003

More publications

CIISB Research Highlights

the best of science obtained using CIISB Core Facilities

  • Nature Communications 2024-2

    Nature Communications 2024-2

    Tomáš Kouba Research Group

    Structural details of the highlighted MsmIMPDH monomer.

    Significance

    Allosteric regulation of inosine 5′-monophosphate dehydrogenase (IMPDH), an essential enzyme of purine metabolism, contributes to the homeostasis of adenine and guanine nucleotides. However, the precise molecular mechanism of IMPDH regulation in bacteria remains unclear. Using biochemical and cryo-EM approaches, we reveal the intricate molecular mechanism of the IMPDH allosteric regulation in mycobacteria. The enzyme is inhibited by both GTP and (p)ppGpp, which bind to the regulatory CBS domains and, via interactions with basic residues in hinge regions, lock the catalytic core domains in a compressed conformation. This results in occlusion of inosine monophosphate (IMP) substrate binding to the active site and, ultimately, inhibition of the enzyme. The GTP and (p)ppGpp allosteric effectors bind to their dedicated sites but stabilize the compressed octamer by a common mechanism. Inhibition is relieved by the competitive displacement of GTP or (p)ppGpp by ATP allowing IMP-induced enzyme expansion. The structural knowledge and mechanistic understanding presented here open up new possibilities for the development of allosteric inhibitors with antibacterial potential.

    Bulvas, O., Knejzlík, Z., Sýs, J. et al. Deciphering the allosteric regulation of mycobacterial inosine-5′-monophosphate dehydrogenase.
    Nat Commun 15, 6673 (2024). https://doi.org/10.1038/s41467-024-50933-6
  • Proceedings of the National Academy of Sciences of the United States of America 2024

    Proceedings of the National Academy of Sciences of the United States of America 2024

    GAG-binding sites of Sema2b. Ribbon representation of Sema2bΔC in complex with SOS, the sema domain is shown in orange, the PSI domain in blue, the Ig-like domain in red, and SOS is shown in stick representation. A 66-residue long C-terminal tail, which was omitted from the construct used for crystallization, is represented by a dashed gray line. The C-terminal central helix predicted by AlphaFold is shown in green. Schematic domain organization of Sema2b is shown below the ribbon representation, highlighting the locations of SOS binding sites with yellow stars. The high-affinity binding site is indicated by a violet star.

    Daniel Rozbesky Research Group

    Significance

    The development of the nervous system relies on precise axon guidance, orchestrated by cues like semaphorins. These cues not only engage their cognate receptors but also interact with extracellular matrix components like proteoglycans, whose role remains poorly understood. Our study reveals that secreted semaphorins bind specifically to proteoglycan glycosaminoglycan chains via multiple sites, with an essential high-affinity site located at the C-terminal tail. Deleting this site disrupts semaphorin activity in guiding olfactory receptor neuron axons in vivo. We propose that secreted semaphorins attach to cell surfaces via proteoglycan interactions, aiding their recognition by axon receptors.

    NOURISANAMI, Farahdokht; SOBOL, Margarita; LI, Zhuoran; HORVATH, Matej; KOWALSKA, Karolina et al. Molecular mechanisms of proteoglycan-mediated semaphorin signaling in axon guidance.

    Proceedings of the National Academy of Sciences of the United States of America, 2024, e24202755121, https://doi.org/10.1073/pnas.2402755121

  • Nucleic Acid Research 2024

    Nucleic Acid Research 2024

    Pavlina Rezacova Research Group

    DNA binding to CggR in the cryo-EM structure. Model of the CggR–OLR biological unit fitted to a cryo-EM map.

    Significance

    The SorC family of transcriptional regulators plays a crucial role in controlling the carbohydrate metabolism and quorum sensing. We employed an integrative approach combining X-ray crystallography and cryo-electron microscopy to investigate architecture and functional mechanism of two prototypical representatives of two sub-classes of the SorC family: DeoR and CggR from Bacillus subtilis. Despite possessing distinct DNA-binding domains, both proteins form similar tetrameric assemblies when bound to their respective DNA operators. Structural analysis elucidates the process by which the CggR-regulated gapA operon is derepressed through the action of two effectors: fructose-1,6-bisphosphate and newly confirmed dihydroxyacetone phosphate. Our findings provide the first comprehensive understanding of the DNA binding mechanism of the SorC-family proteins, shedding new light on their functional characteristics.

    Soltysova M. et al. Structural characterization of two prototypical repressors of SorC family reveals tetrameric assemblies on DNA and mechanism of function

    Nucleic Acid Research 2024, 52(12), 7305-20, DOI: 10.1093/nar/gkae434

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 October

“Science never solves a problem without creating ten more.”

George Bernard Shaw

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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