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  • 1.
    Aurelius, Oskar
    et al.
    Lund University.
    Johansson, Renzo
    Lund University.
    Bågenholm, Viktoria
    Lund University.
    Lundin, Daniel
    Stockholm University.
    Tholander, Fredrik
    Karolinska Institutet.
    Balhuizen, Alexander
    Lund University.
    Beck, Tobias
    University of Göttingen, Germany.
    Sahlin, Margareta
    Stockholm University.
    Sjöberg, Britt-Marie
    Stockholm University.
    Mulliez, Etienne
    Institut de Recherches en Technologies et Sciences pour le Vivant (iRTSV), France.
    Logan, Derek T.
    Lund University.
    The Crystal Structure of Thermotoga maritima Class III Ribonucleotide Reductase Lacks a Radical Cysteine Pre-Positioned in the Active Site2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0128199Article in journal (Refereed)
    Abstract [en]

    Ribonucleotide reductases (RNRs) catalyze the reduction of ribonucleotides to deoxyribonucleotides, the building blocks for DNA synthesis, and are found in all but a few organisms. RNRs use radical chemistry to catalyze the reduction reaction. Despite RNR having evolved several mechanisms for generation of different kinds of essential radicals across a large evolutionary time frame, this initial radical is normally always channelled to a strictly conserved cysteine residue directly adjacent to the substrate for initiation of substrate reduction, and this cysteine has been found in the structures of all RNRs solved to date. We present the crystal structure of an anaerobic RNR from the extreme thermophile Thermotoga maritima (tmNrdD), alone and in several complexes, including with the allosteric effector dATP and its cognate substrate CTP. In the crystal structure of the enzyme as purified, tmNrdD lacks a cysteine for radical transfer to the substrate pre-positioned in the active site. Nevertheless activity assays using anaerobic cell extracts from T. maritima demonstrate that the class III RNR is enzymatically active. Other genetic and microbiological evidence is summarized indicating that the enzyme is important for T. maritima. Mutation of either of two cysteine residues in a disordered loop far from the active site results in inactive enzyme. We discuss the possible mechanisms for radical initiation of substrate reduction given the collected evidence from the crystal structure, our activity assays and other published work. Taken together, the results suggest either that initiation of substrate reduction may involve unprecedented conformational changes in the enzyme to bring one of these cysteine residues to the expected position, or that alternative routes for initiation of the RNR reduction reaction may exist. Finally, we present a phylogenetic analysis showing that the structure of tmNrdD is representative of a new RNR subclass IIIh, present in all Thermotoga species plus a wider group of bacteria from the distantly related phyla Firmicutes, Bacteroidetes and Proteobacteria.

  • 2.
    Friedman, Ran
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Boye, Kjetil
    Flatmark, Kjersti
    Molecular modelling and simulations in cancer research2013In: Biochimica et Biophysica Acta. CR. Reviews on Cancer, ISSN 0304-419X, E-ISSN 1879-2561, Vol. 1836, no 1, p. 1-14Article, review/survey (Refereed)
    Abstract [en]

    The complexity of cancer and the vast amount of experimental data available have made computer-aided approaches necessary. Biomolecular modelling techniques are becoming increasingly easier to use, whereas hardware and software are becoming better and cheaper. Cross-talk between theoretical and experimental scientists dealing with cancer-research from a molecular approach, however, is still uncommon. This is in contrast to other fields, such as amyloid-related diseases, where molecular modelling studies are widely acknowledged. The aim of this review paper is therefore to expose some of the more common approaches in molecular modelling to cancer scientists in simple terms, illustrating success stories while also revealing the limitations of computational studies at the molecular level.

  • 3.
    Friedman, Ran
    et al.
    University of Zürich, Switzerland.
    Caflisch, A
    On the orientation of the catalytic dyad in aspartic proteases2010In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 78, no 6, p. 1575-1582Article in journal (Refereed)
    Abstract [en]

    The recent re-refinement of the X-ray structure of apo plasmepsin II from Plasmodium falciparum suggests that the two carboxylate groups in the catalytic dyad are noncoplanar, (Robbins et al., Acta Crystallogr D Biol Crystallogr 2009;65: 294–296) in remarkable contrast with the vast majority of structures of aspartic proteases. Here, evidence for the noncoplanarity of the catalytic aspartates is provided by analysis of multiple explicit water molecular dynamics (MD) simulations of plasmepsin II, human β-secretase, and HIV-protease. In the MD runs of plasmepsin II, the angle between the planes of the two carboxylates of the catalytic dyad is almost always in the range 60°–120°, in agreement with the perpendicular orientation in the re-refined X-ray structure. The noncoplanar arrangement is prevalent also in the β-secretase simulations, as well as in the runs with the inhibitor-bound proteases. Quantum-mechanics calculations provide further evidence that before catalysis the noncoplanar arrangement is favored energetically in eukaryotic aspartic proteases. Remarkably, the coplanar orientation of the catalytic dyad is observed in MD simulations of HIV-protease at 100 K but not at 300 K, which indicates that the noncoplanar arrangement is favored by conformational entropy. This finding suggests that the coplanar orientation in the crystal structures of apo aspartic proteases is promoted by the very low temperature used for data collection (usually around 100 K).

  • 4. Friedman, Ran
    et al.
    Caflisch, A
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Pepsinogen-like activation intermediate of plasmepsin II revealed by molecular dynamics analysis2008In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 73, no 4, p. 814-827Article in journal (Refereed)
  • 5.
    Friedman, Ran
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Caflisch, Amedeo
    Department of Biochemistry, University of Zürich.
    Surfactant Effects on Amyloid Aggregation Kinetics2011In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 414, p. 303-312Article in journal (Refereed)
    Abstract [en]

    There is strong experimental evidence of the influence of surfactants (e.g., fatty acids) on the kinetics of amyloid fibril formation. However, the structures of mixed assemblies and interactions between surfactants and fibril-forming peptides are still not clear. Here, coarse-grained simulations are employed to study the aggregation kinetics of amyloidogenic peptides in the presence of amphiphilic lipids. The simulations show that the lower the fibril formation propensity of the peptides, the higher the influence of the surfactants on the peptide self-assembly kinetics. In particular, the lag phase of weakly aggregating peptides increases because of the formation of mixed oligomers, which are promoted by hydrophobic interactions and favorable entropy of mixing. A transient peak in the number of surfactants attached to the growing fibril is observed before reaching the mature fibril in some of the simulations. This peak originates from transient fibrillar defects consisting of exposed hydrophobic patches on the fibril surface, which provide a possible explanation for the temporary maximum of fluorescence observed sometimes in kinetic traces of the binding of small-molecule dyes to amyloid fibrils.

  • 6. Ganoth, A.
    et al.
    Nachliel, E.
    Friedman, Ran
    Tel AvivUniversity, Israel.
    Gutman, M.
    Molecular dynamics study of a calmodulin-like protein with an IQ peptide: spontaneous refolding of the protein around the peptide2006In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 64, no 1, p. 133-146Article in journal (Refereed)
  • 7. Ganoth, Assaf
    et al.
    Friedman, Ran
    Nachliel, Esther
    Gutman, Menachem
    A molecular dynamics study and free energy analysis of complexes between the Mlc1p protein and two IQ motif peptides2006In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 91, no 7, p. 2436-2450Article in journal (Refereed)
  • 8. Johansson, Renzo
    et al.
    Torrents, Eduard
    Lundin, Daniel
    Stockholm University.
    Sprenger, Janina
    Sahlin, Margareta
    Sjöberg, Britt-Marie
    Stockholm University.
    Logan, Derek T.
    Lund University.
    High-resolution crystal structures of the flavoprotein NrdI in oxidized and reduced states – an unusual flavodoxin2010In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 277, no 20, p. 4265-4277Article in journal (Refereed)
    Abstract [en]

    The small flavoprotein NrdI is an essential component of the class Ib ribonucleotide reductase system in many bacteria. NrdI interacts with the class Ib radical generating protein NrdF. It is suggested to be involved in the rescue of inactivated diferric centres or generation of active dimanganese centres in NrdF. Although NrdI bears a superficial resemblance to flavodoxin, its redox properties have been demonstrated to be strikingly different. In particular, NrdI is capable of two-electron reduction, whereas flavodoxins are exclusively one-electron reductants. This has been suggested to depend on a lesser destabilization of the negatively-charged hydroquinone state than in flavodoxins. We have determined the crystal structures of NrdI from Bacillus anthracis, the causative agent of anthrax, in the oxidized and semiquinone forms, at resolutions of 0.96 and 1.4 Å, respectively. These structures, coupled with analysis of all curated NrdI sequences, suggest that NrdI defines a new structural family within the flavodoxin superfamily. The conformational behaviour of NrdI in response to FMN reduction is very similar to that of flavodoxins, involving a peptide flip in a loop near the N5 atom of the flavin ring. However, NrdI is much less negatively charged than flavodoxins, which is expected to affect its redox properties significantly. Indeed, sequence analysis shows a remarkable spread in the predicted isoelectric points of NrdIs, from approximately pH 4–10. The implications of these observations for class Ib ribonucleotide reductase function are discussed.

  • 9.
    Katona, Gergely
    et al.
    University of Gothenburg, Sweden.
    Lundholm, Ida
    University of Gothenburg, Sweden.
    Rodilla, Helena
    Chalmers University of Technology, Sweden.
    Garcia-Bonete, Maria-Jose
    University of Gothenburg, Sweden.
    Duelli, Annette
    University of Gothenburg, Sweden.
    Wahlgren, Weixiao Y
    University of Gothenburg, Sweden.
    Bourenkov, Gleb
    DESY, European Mol Biol Lab Hamburg Outstn, Germany.
    Vukusic, Josip
    Chalmers University of Technology, Sweden.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Schneider, Thomas
    DESY, European Mol Biol Lab Hamburg Outstn, Germany.
    Stake, Jan
    Chalmers University of Technology, Sweden.
    Bayesian analysis of non-thermal structural changes induced by terahertz radiation in protein crystals2016In: 2016 41ST INTERNATIONAL CONFERENCE ON INFRARED, MILLIMETER, AND TERAHERTZ WAVES (IRMMW-THZ), IEEE conference proceedings, 2016Conference paper (Refereed)
    Abstract [en]

    We have periodically (25ms on - 25ms off) illuminated lysozyme crystals with 0.4 THz radiation and simultaneously monitored their X-ray diffraction intensity in order to study non-thermal structural changes in the protein. In this work we analyze the X-ray scaled and unmerged diffraction intensity observations using a multivariate Bayesian model in order to improve the accuracy of the intensity estimates. The diffraction intensity pairs of the illuminated and non-illuminated state show a predominantly positive correlation. The correlation decreases with increasing resolution suggesting that finer slicing and faster sampling of the rocking curve may further improve the accuracy and effect size of structure factor amplitude differences, making the interpretation of structural changes more straightforward. The improved analysis retains the most important structural features described previously (in helix 3) and provide addition details about the B-factor changes close to the substrate binding site.

  • 10.
    Lundholm, Ida V
    et al.
    University of Gothenburg.
    Rodilla, Helena
    Chalmers University of Technology.
    Wahlgren, Weixiao Y.
    University of Gothenburg.
    Duelli, Annette
    University of Gothenburg.
    Bourenkov, Gleb
    European Molecular Biology Laboratory Hamburg Outstation, Germany.
    Vukusic, Josip
    Chalmers University of Technology.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Stake, Jan
    Chalmers University of Technology.
    Schneider, Thomas
    European Molecular Biology Laboratory Hamburg Outstation, Germany.
    Katona, Gergely
    University of Gothenburg.
    Terahertz radiation induces non-thermal structural changes associated with Fröhlich condensation in a protein crystal2015In: Structural Dynamics, E-ISSN 2329-7778, Vol. 2, no 5, article id 054702Article in journal (Refereed)
    Abstract [en]

    Whether long-range quantum coherent states could exist in biological systems, and beyond low-temperature regimes where quantum physics is known to be applicable, has been the subject to debate for decades. It was proposed by Fröhlich that vibrational modes within protein molecules can order and condense into a lowest-frequency vibrational mode in a process similar to Bose-Einstein condensation, and thus that macroscopic coherence could potentially be observed in biological systems. Despite the prediction of these so-called Fröhlich condensates almost five decades ago, experimental evidence thereof has been lacking. Here, we present the first experimental observation of Fröhlich condensation in a protein structure. To that end, and to overcome the challenges associated with probing low-frequency molecular vibrations in proteins(which has hampered understanding of their role in proteins' function), we combined terahertz techniques with a highly sensitive X-ray crystallographic method to visualize low-frequency vibrational modes in the protein structure of hen-egg white lysozyme. We found that 0.4 THz electromagnetic radiation induces non-thermal changes in electron density. In particular, we observed a local increase of electron density in a long α-helix motif consistent with a subtle longitudinal compression of the helix. These observed electron density changes occur at a low absorption rate indicating that thermalization of terahertz photons happens on a micro- to milli-second time scale, which is much slower than the expected nanosecond time scale due to damping of delocalized low frequency vibrations. Our analyses show that the micro- to milli-second lifetime of the vibration can only be explained by Fröhlich condensation, a phenomenon predicted almost half a century ago, yet never experimentally confirmed.

  • 11.
    Mohlin, Camilla
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Delbro, Dick
    Örebro University.
    Kvanta, Anders
    Karolinska Institutet.
    Johansson, Kjell
    Kristianstad University.
    Evaluation of Congo Red Staining in Degenerating Porcine Photoreceptors In Vitro: Protective Effects by Structural and Trophic Support2018In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 66, no 9Article in journal (Refereed)
    Abstract [en]

    Congo red (CR) is a histological stain used for the detection of extracellular amyloids mediating various neurodegenerative diseases. Given that damaged photoreceptors appear to degenerate similarly to other nerve cells, CR staining was evaluated in experimentally injured porcine retina. CR staining appeared mostly as discrete cytosolic deposits with no obvious plaque formation during the investigated time period. Increases of CR labeling coincided temporally with the known accumulation of mislocalized opsins and increases of cell death. Coculture, either with human retinal pigment epithelium (ARPE) or human neural progenitor (ReN) cells, was accompanied by a significant reduction of CR labeling. Of particular interest was the reduction of CR labeling in cone photoreceptors, which are important for the perception of color and fine details and afflicted in age-related macular degeneration (AMD). Electron microscopy revealed inclusions in the inner segment, cell body, and occasionally synaptic terminals of photoreceptor cells in cultured specimens. Closer examinations indicated the presence of different types of inclusions resembling protein aggregates as well as inclusion bodies. The current results indicate that injury-related response resulted in accumulation of CR deposits in photoreceptor cells, and that trophic and/or structural support attenuated this response.

  • 12.
    Rosengren, K. Johan
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences. University of Queensland.
    Haugaard Jönsson, Linda M.
    University of Kalmar, School of Pure and Applied Natural Sciences. University of Copenhagen.
    Bengtsson, Elina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Daly, Norelle
    University of Queensland.
    Fornander, Liselotte M
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Qu, Xiaoqing
    University of California.
    Tanabe, Hiroki
    University of California.
    Craik, David J
    University of Queensland.
    Ouellette, Andre J
    University of California.
    Structural and Functional Role of the Conserved Salt-Bridge in the Mammalian alpha-Defensin Cryptdin-4.2007Conference paper (Other academic)
  • 13. Seeber, M
    et al.
    Felline, A
    Raimondi, F
    Muff, S
    Friedman, Ran
    Univ Zurich, Dept Biochem, CH-8057 Zurich, Switzerland .
    Rao, F
    Caflisch, A
    Fanelli, F
    Wordom: a user-friendly program for the analysis of molecular conformations, trajectories, and free energy surfaces2011In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 32, no 6, p. 1183-1194Article in journal (Refereed)
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