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CIISB Research Highlights Archive

  • Springer Nature 2026

    Springer Nature 2026

    Department of Parasitology, Charles University

    Significance

    The leishmaniases are vector-borne diseases transmitted by female sand flies (Phlebotomus spp.). To assess Leishmania transmission risk, host exposure can be monitored via antibodies against vector salivary proteins. This study developed ELISA assays using recombinant salivary antigens from P. tobbi and P. papatasi to detect specific antibodies in dog sera from endemic areas in Türkiye.

    Kolářová et al.: Development of new screening tools to evaluate dog exposure to Phlebotomus tobbi and Phlebotomus papatasi sand flies

    Parasites & Vectors, DOI: 10.1186/s13071-026-07286-4

  • Chemistry Europe 2026

    Chemistry Europe 2026

    Department of Biochemistry and Microbiology, Institute of Microbiology of the Czech Academy of Sciences

    Significance

    This study focuses on the structure‑guided engineering of a fungal quercetin 2,3‑dioxygenase to redirect its activity toward artificial flavonols. By combining structural analysis with targeted mutagenesis, the work demonstrates how substrate specificity and catalytic performance can be systematically modified. The results provide insight into structure–function relationships in metalloenzymes and highlight their potential use in tailored biocatalytic applications.

    Kotik et al.: Redirecting a fungal quercetin 2,3‑dioxygenase toward artificial flavonols

    ChemCatChem, DOI: 10.1002/cctc.202501823

  • Nature Communications 2025

    Nature Communications 2025

    Zdenek Lansky, Head of group Structural proteins and their complexes

    RGC-specific OPTN C-terminus truncation leads to progressive RGC and ON degeneration.

    Significance

    This study investigates the role of optineurin in axonal mitochondrial transport and highlights its importance for neuronal maintenance and recovery. By analysing mechanisms that support mitochondrial delivery to axons, the work provides new insight into cellular processes underlying neuroprotection and axon regeneration. The findings contribute to a broader understanding of how intracellular transport pathways influence neuronal survival and may be relevant for research into neurodegenerative and injury‑related conditions.

    Liu et al.: Optineurin‑facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration

    Nature Communications, DOI: 10.1038/s41467-025-57135-8

  • Nature Catalysis 2025

    Nature Catalysis 2025

    P. Wendler Research Group

    Cryo-EM structures of the as-isolated and reduced CODH–ACS.

    Significance

    Catalytic metal clusters play critical roles in important enzymatic pathways such as carbon fixation and energy conservation. However, how ligand binding to the active-site metal regulates conformational changes critical for enzyme function is often not well understood. One carbon fixation pathway that relies heavily on metalloenzymes is the reductive acetyl-coenzyme A (acetyl-CoA) pathway. In this study, we investigated the catalysis of the last step of the reductive acetyl-CoA pathway by the CO-dehydrogenase (CODH)-acetyl-CoA synthase (ACS) complex from Carboxydothermushydrogenoformans, focusing on how ligand binding to the nickel atom in the active site affects the conformational equilibrium of the enzyme. We captured six intermediate states of the enzyme by cryo-electron microscopy, with resolutions of 2.5-1.9A, and visualized reaction products bound to cluster A (an Ni,Ni-[4Fe4S] cluster) and identified several previously uncharacterized conformational states of CODH-ACS. The structures demonstrate how substrate binding controls conformational changes in the ACS subunit to prepare for the next catalytic step. 

    Ruickoldt J. et al.: Ligand binding to a Ni-Fe cluster orchestrates conformational changes of the CO-dehydrogenase-acetyl-CoA synthase complex

    Nature Catalysis 2025, 10.1038/s41929-025-01365-y 

  • Angewandte Chemie Int. Ed. 2025

    Angewandte Chemie Int. Ed. 2025

    O. Jurcek Research Group 

    Chiral Pd6L8 or Pd12L16 cages.

    Significance

    The rational design and selective self-assembly of flexible and unsymmetric ligands into large coordination complexes is an eminent challenge in supramolecular coordination chemistry. Here, we present the coordination-driven self-assembly of natural ursodeoxycholic-bile-acid-derived unsymmetric tris-pyridyl ligand (L) resulting in the selective and switchable formation of chiral stellated Pd6L8 and Pd12L16 cages. The selectivity of the cage originates in the adaptivity and flexibility of the arms of the ligand bearing pyridyl moieties. The interspecific transformations can be controlled by changes in the reaction conditions. The orientational self-sorting of L into a single constitutional isomer of each cage, i.e., homochiral quadruple and octuple right-handed helical species, was confirmed by a combination of molecular modelling and circular dichroism. The cages, derived from natural amphiphilic transport molecules, mediate the higher cellular uptake and increase the anticancer activity of bioactive palladium cations as determinedin studies using in vitro 3D spheroids of the human hepatic cells HepG2. 

    Chattopadhyay S. et al.: Flexibility-Aided Orientational Self-Sorting and Transformations of Bioactive Homochiral Cuboctahedron Pd12L16

    Angew. Chem. Int. Ed. 2025, 10.1002/anie.202513902

  • Science Advances 2025

    Science Advances 2025

    C. Barinka Research Group

    The cryo-EM reconstruction of the TTLL11/MT complex.

    Significance

    Microtubules (MTs) undergo diverse posttranslational modifications that regulate their structural and functional properties. Among these, polyglutamylation-a dominant and conserved modification targeting unstructured tubulin C-terminal tails-plays a pivotal role in defining the tubulin code. Here, we describe a mechanism by which tubulin tyrosine ligase-like 11 (TTLL11) expands and diversifies the code. Cryo-electron microscopy revealed a unique bipartite MT recognition strategy wherein TTLL11 binding and catalytic domains engage adjacent MT protofilaments. Biochemical and cellular assays identifiedpreviously uncharacterized polyglutamylation patterns, showing that TTLL11 directly extends the primary polypeptide chains of alpha- and beta-tubulin in vitro, challenging the prevailing paradigms emphasizing lateral branching. Moreover, cell-based and in vivo data suggest a cross-talk between polyglutamylation and the detyrosination/tyrosination cycle likely linked to the TTLL11-mediated elongation of the primary alpha-tubulin chain. These findings unveil an unrecognized layer of complexity within the tubulin code and offer mechanistic insights into the molecular basis of functional specialization of MT cytoskeleton.

    Campbell J. et al.: Mechanistic insights into TTLL11 polyglutamylase-mediated primary tubulin chain elongation

    Science Advances 2025, 10.1126/sciadv.adw1561

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Highlights of Coronavirus Structural Studies

6 Apr 2022

Deep learning guided optimization of human antibody against SARS-CoV-2 variants with broad neutralization (PNAS)

The ability of viruses to mutate and evade the human immune system and neutralizing antibodies remains an obstacle to antiviral and vaccine development. Many neutralizing antibodies, including some approved for emergency use authorization (EUA), reduced or lost activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Here, we introduce a geometric deep learning algorithm that efficiently enhances antibody affinity to achieve broader and more potent neutralizing activity against such variants. We demonstrate the utility of our approach on a human antibody P36-5D2, which is effective against SARS-CoV-2 Alpha, Beta, and Gamma but not Delta. We show that our geometric neural network model optimizes this antibody's complementaritydetermining region (CDR) sequences to improve its binding affinity against multiple SARS-CoV-2 variants. Through iterative optimization of the CDR regions and experimental measurements, we enable expanded antibody breadth and improved potency by similar to 10to 600-fold against SARS-CoV-2 variants, including Delta. We have also demonstrated that our approach can identify CDR changes that alleviate the impact of two Omicron mutations on the epitope. These results highlight the power of our deep learning approach in antibody optimization and its potential application to engineering other protein molecules. Our optimized antibodies can potentially be developed into antibody drug candidates for current and emerging SARS-CoV-2 variants.

6 Apr 2022

Ensemble cryo-EM reveals conformational states of the nsp13 helicase in the SARS-CoV-2 helicase replication–transcription complex (Nature Structural and Molecular Biology)

The SARS-CoV-2 nonstructural proteins coordinate genome replication and gene expression. Structural analyses revealed the basis for coupling of the essential nsp13 helicase with the RNA-dependent RNA polymerase (RdRp) where the holo-RdRp and RNA substrate (the replication–transcription complex or RTC) associated with two copies of nsp13 (nsp132–RTC). One copy of nsp13 interacts with the template-RNA in an opposing polarity to the RdRp and is envisaged to drive the RdRp backward on the RNA template (backtracking), prompting questions as to how the RdRp can efficiently synthesize RNA in the presence of nsp13. Here we use cryogenic-electron microscopy and molecular dynamics simulations to analyze the nsp132–RTC, revealing four distinct conformational states of the helicases. The results indicate a mechanism for the nsp132–RTC to turn backtracking on and off, using an allosteric mechanism to switch between RNA synthesis or backtracking in response to stimuli at the RdRp active site.

6 Apr 2022

Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants (Nature Communications)

The Delta and Kappa variants of SARS-CoV-2 co-emerged in India in late 2020, with the Delta variant underlying the resurgence of COVID-19, even in countries with high vaccination rates. In this study, we assess structural and biochemical aspects of viral fitness for these two variants using cryo-electron microscopy (cryo-EM), ACE2-binding and antibody neutralization analyses. Both variants demonstrate escape of antibodies targeting the N-terminal domain, an important immune hotspot for neutralizing epitopes. Compared to wild-type and Kappa lineages, Delta variant spike proteins show modest increase in ACE2 affinity, likely due to enhanced electrostatic complementarity at the RBD-ACE2 interface, which we characterize by cryo-EM. Unexpectedly, Kappa variant spike trimers form a structural head-to-head dimer-of-trimers assembly, which we demonstrate is a result of the E484Q mutation and with unknown biological implications. The combination of increased antibody escape and enhanced ACE2 binding provides an explanation, in part, for the rapid global dominance of the Delta variant.

5 Jan 2022

The atomic portrait of SARS-CoV-2 as captured by cryo-electron microscopy (Journal of Cellular and Molecular Medicine)

Transmission electron microscopy has historically been indispensable for virology research, as it offers unique insight into virus function. In the past decade, as cryo-electron microscopy (cryo-EM) has matured and become more accessible, we have been able to peer into the structure of viruses at the atomic level and understand how they interact with the host cell, with drugs or with antibodies. Perhaps, there was no time in recent history where cryo-EM was more needed, as SARS-CoV-2 has spread around the globe, causing millions of deaths and almost unquantifiable economic devastation. In this concise review, we aim to mark the most important contributions of cryo-EM to understanding the structure and function of SARS-CoV-2 proteins, from surface spikes to the virus core and from virus-receptor interactions to antibody binding.

5 Jan 2022

Membrane fusion and immune evasion by the spike protein of SARS-CoV-2 Delta variant (Science)

The Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has outcompeted previously prevalent variants and become a dominant strain worldwide. We report the structure, function, and antigenicity of its full-length spike (S) trimer as well as those of the Gamma and Kappa variants, and compare their characteristics with the G614, Alpha, and Beta variants. Delta S can fuse membranes more efficiently at low levels of cellular receptor angiotensin converting enzyme 2 (ACE2), and its pseudotyped viruses infect target cells substantially faster than the other five variants, possibly accounting for its heightened transmissibility. Each variant shows different rearrangement of the antigenic surface of the amino-terminal domain of the S protein but only makes produces changes in the receptor binding domain (RBD), making the RBD a better target for therapeutic antibodies.

5 Jan 2022

Conformational dynamics of the Beta and Kappa SARS-CoV-2 spike proteins and their complexes with ACE2 receptor revealed by cryo-EM (Nature Communications)

The emergence of SARS-CoV-2 Kappa and Beta variants with enhanced transmissibility and resistance to neutralizing antibodies has created new challenges for the control of the ongoing COVID-19 pandemic. Understanding the structural nature of Kappa and Beta spike (S) proteins and their association with ACE2 is of significant importance. Here we present two cryo-EM structures for each of the Kappa and Beta spikes in the open and open-prone transition states. Compared with wild-type (WT) or G614 spikes, the two variant spikes appear more untwisted/open especially for Beta, and display a considerable population shift towards the open state as well as more pronounced conformational dynamics. Moreover, we capture four conformational states of the S-trimer/ACE2 complex for each of the two variants, revealing an enlarged conformational landscape for the Kappa and Beta S-ACE2 complexes and pronounced population shift towards the three RBDs up conformation. These results implicate that the mutations in Kappa and Beta may modify the kinetics of receptor binding and viral fusion to improve virus fitness. Combined with biochemical analysis, our structural study shows that the two variants are enabled to efficiently interact with ACE2 receptor despite their sensitive ACE2 binding surface is modified to escape recognition by some potent neutralizing MAbs. Our findings shed new light on the pathogenicity and immune evasion mechanism of the Beta and Kappa variants.

10 Nov 2021

Molecular basis of immune evasion by the Delta and Kappa SARS-CoV-2 variants (Science)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission leads to the emergence of variants, including the B.1.617.2 (Delta) variant of concern which is causing a new wave of infections and has become globally dominant. D. Veesler et.al. show that these variants dampen the in vitro potency of vaccine-elicited serum neutralizing antibodies and provide a structural framework for describing their immune evasion. Mutations in the B.1.617.1 (Kappa) and B.1.617.2 (Delta) spike glycoproteins abrogate recognition by several monoclonal antibodies via alteration of key antigenic sites, including remodeling of the B.1.617.2 (Delta) N-terminal domain. They determined electron cryo-microscopy (cryo-EM) structures of the B.1.617.1 and B.1.617.2 S glycoproteins to gain insights into their reduced antibody sensitivity and provide a structural framework to understand the role of shared and distinct mutations.  The ACE2 binding affinities of the B.1.617.1 (Kappa) and B.1.617.2 (Delta) receptor-binding domains are comparable to the Wuhan-Hu-1 isolate whereas B.1.617.2+ (Delta+) exhibits markedly reduced affinity.

8 Nov 2021

Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332 (Protein & Cell)

The crystal structure of SARS-CoV-2 Mpro in complex with PF-07321332 at 1.6 Å resolution was determined. PF-07321332 is a reversible covalent inhibitor carrying a nitrile warhead that targets SARS-CoV-2 Mpro. The overall structure of SARS-CoV-2 Mpro is a functional dimer, consistent with previous findings. The 1.6-Å crystal structure of SARS-CoV-2 Mpro in complex with the protease inhibitor PF-07321332 reveals critical insight for pharmaceutical development. With the emergence of SARS-CoV-2 variants with immune evasion, therapeutics targeting a conserved but essential viral target among the variants may synergize the COVID-19 vaccines. The improved oral bioavailability would enhance the clinical utility of PF-07321332 as a therapeutic to prevent progression among early-stage non-hospitalized patients or as a prophylaxis in the pre- and post-exposure setting. Further optimization of such covalent peptidomimetic inhibitors would generate potent drugs to contain the current COVID-19 pandemic and increase public health preparedness for potential future pandemic.

8 Nov 2021

NMR Spectroscopy of the Main Protease of SARS-CoV-2 and Fragment-Based Screening Identify Three Protein Hotspots and an Antiviral Fragment (Angewandte Chemie Int. Ed)

The main protease (3CLp) of the SARS-CoV-2, the causative agent for the COVID-19 pandemic, is one of the main targets for drug development. To be active, 3CLp relies on a complex interplay between dimerization, active site flexibility, and allosteric regulation. The deciphering of these mechanisms is a crucial step to enable the search for inhibitors. In this context, using NMR spectroscopy, J. Charton, X. Hanoulle et. al. studied the conformation of dimeric 3CLp from the SARS-CoV-2 and monitored ligand binding, based on NMR signal assignments. They performed a fragment-based screening that led to the identification of 38 fragment hits. Their binding sites showed three hotspots on 3CLp, two in the substrate binding pocket and one at the dimer interface. F01 is a non-covalent inhibitor of the 3CLp and has antiviral activity in SARS-CoV-2 infected cells. This study sheds light on the complex structure-function relationships of 3CLp and constitutes a strong basis to assist in developing potent 3CLp inhibitors.

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