| 1. |
- Akishiba, Misao, et al.
(author)
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Cytosolic antibody delivery by lipid-sensitive endosomolytic peptide
- 2017
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In: Nature Chemistry. - 1755-4330 .- 1755-4349. ; 9:8, s. 751-761
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Journal article (peer-reviewed)abstract
- One of the major obstacles in intracellular targeting using antibodies is their limited release from endosomes into the cytosol. Here we report an approach to deliver proteins, which include antibodies, into cells by using endosomolytic peptides derived from the cationic and membrane-lytic spider venom peptide M-lycotoxin. The delivery peptides were developed by introducing one or two glutamic acid residues into the hydrophobic face. One peptide with the substitution of leucine by glutamic acid (L17E) was shown to enable a marked cytosolic liberation of antibodies (immunoglobulins G (IgGs)) from endosomes. The predominant membrane-perturbation mechanism of this peptide is the preferential disruption of negatively charged membranes (endosomal membranes) over neutral membranes (plasma membranes), and the endosomolytic peptide promotes the uptake by inducing macropinocytosis. The fidelity of this approach was confirmed through the intracellular delivery of a ribosome-inactivation protein (saporin), Cre recombinase and IgG delivery, which resulted in a specific labelling of the cytosolic proteins and subsequent suppression of the glucocorticoid receptor-mediated transcription. We also demonstrate the L17E-mediated cytosolic delivery of exosome-encapsulated proteins.
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| 2. |
- Albinsson, Bo, 1963
(author)
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ENERGY TRANSFER On the right path
- 2011
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In: Nature Chemistry. - : Springer Science and Business Media LLC. - 1755-4349 .- 1755-4330. ; 3:4, s. 269-270
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Journal article (other academic/artistic)
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| 3. |
- Aspuru-Guzik, A., et al.
(author)
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Charting a course for chemistry
- 2019
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In: Nature Chemistry. - : Springer Science and Business Media LLC. - 1755-4330 .- 1755-4349. ; 11:4, s. 286-294
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Journal article (peer-reviewed)
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| 4. |
- Bakulin, Artem A, et al.
(author)
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Real-time observation of multiexcitonic states in ultrafast singlet fission using coherent 2D electronic spectroscopy.
- 2016
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In: Nature Chemistry. - : Springer Science and Business Media LLC. - 1755-4330 .- 1755-4349. ; 8:1, s. 16-23
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Journal article (peer-reviewed)abstract
- Singlet fission is the spin-allowed conversion of a spin-singlet exciton into a pair of spin-triplet excitons residing on neighbouring molecules. To rationalize this phenomenon, a multiexcitonic spin-zero triplet-pair state has been hypothesized as an intermediate in singlet fission. However, the nature of the intermediate states and the underlying mechanism of ultrafast fission have not been elucidated experimentally. Here, we study a series of pentacene derivatives using ultrafast two-dimensional electronic spectroscopy and unravel the origin of the states involved in fission. Our data reveal the crucial role of vibrational degrees of freedom coupled to electronic excitations that facilitate the mixing of multiexcitonic states with singlet excitons. The resulting manifold of vibronic states drives sub-100 fs fission with unity efficiency. Our results provide a framework for understanding singlet fission and show how the formation of vibronic manifolds with a high density of states facilitates fast and efficient electronic processes in molecular systems.
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| 5. |
- Björneholm, Olle, et al.
(author)
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Hot spots of radiation damage from extensive water ionization around metal ions
- 2023
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In: Nature Chemistry. - : Springer Nature. - 1755-4330 .- 1755-4349. ; 15:10, s. 1338-1339
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Journal article (other academic/artistic)abstract
- Radiation damage in biological systems by radicals and low-energy electrons formed from water ionization is a consequence of ultrafast processes that follow core-level ionization of hydrated metal ions. More details of the complex pathway are now revealed from the study of aluminium-ion relaxation through sequential electron-transfer-mediated decay.
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| 6. |
- Borne, Kurtis D., et al.
(author)
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Ultrafast electronic relaxation pathways of the molecular photoswitch quadricyclane
- 2024
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In: NATURE CHEMISTRY. - 1755-4330 .- 1755-4349. ; 16, s. 499-505
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Journal article (peer-reviewed)abstract
- The light-induced ultrafast switching between molecular isomers norbornadiene and quadricyclane can reversibly store and release a substantial amount of chemical energy. Prior work observed signatures of ultrafast molecular dynamics in both isomers upon ultraviolet excitation but could not follow the electronic relaxation all the way back to the ground state experimentally. Here we study the electronic relaxation of quadricyclane after exciting in the ultraviolet (201 nanometres) using time-resolved gas-phase extreme ultraviolet photoelectron spectroscopy combined with non-adiabatic molecular dynamics simulations. We identify two competing pathways by which electronically excited quadricyclane molecules relax to the electronic ground state. The fast pathway (<100 femtoseconds) is distinguished by effective coupling to valence electronic states, while the slow pathway involves initial motions across Rydberg states and takes several hundred femtoseconds. Both pathways facilitate interconversion between the two isomers, albeit on different timescales, and we predict that the branching ratio of norbornadiene/quadricyclane products immediately after returning to the electronic ground state is approximately 3:2.
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| 7. |
- Both, P., et al.
(author)
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Discrimination of epimeric glycans and glycopeptides using IM-MS and its potential for carbohydrate sequencing
- 2014
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In: Nature Chemistry. - 1755-4330 .- 1755-4349. ; 6:1, s. 65-74
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Journal article (peer-reviewed)abstract
- Mass spectrometry is the primary analytical technique used to characterize the complex oligosaccharides that decorate cell surfaces. Monosaccharide building blocks are often simple epimers, which when combined produce diastereomeric glycoconjugates indistinguishable by mass spectrometry. Structure elucidation frequently relies on assumptions that biosynthetic pathways are highly conserved. Here, we show that biosynthetic enzymes can display unexpected promiscuity, with human glycosyltransferase pp-a-GanT2 able to utilize both uridine diphosphate N-acetylglucosamine and uridine diphosphate N-acetylgalactosamine, leading to the synthesis of epimeric glycopeptides in vitro. Ion-mobility mass spectrometry ( IM-MS) was used to separate these structures and, significantly, enabled characterization of the attached glycan based on the drift times of the monosaccharide product ions generated following collision-induced dissociation. Finally, ion-mobility mass spectrometry following fragmentation was used to determine the nature of both the reducing and non-reducing glycans of a series of epimeric disaccharides and the branched pentasaccharide Man3 glycan, demonstrating that this technique may prove useful for the sequencing of complex oligosaccharides.
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| 8. |
- Bourrez, Marc, et al.
(author)
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Concerted proton-coupled electron transfer from a metal-hydride complex
- 2015
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In: Nature Chemistry. - 1755-4330 .- 1755-4349. ; 7:2, s. 140-145
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Journal article (peer-reviewed)abstract
- Metal hydrides are key intermediates in the catalytic reduction of protons and CO2 as well as in the oxidation of H-2. In these reactions, electrons and protons are transferred to or from separate acceptors or donors in bidirectional proton-coupled electron transfer (PCET) steps. The mechanistic interpretation of PCET reactions of metal hydrides has focused on the stepwise transfer of electrons and protons. A concerted transfer may, however, occur with a lower reaction barrier and therefore proceed at higher catalytic rates. Here we investigate the feasibility of such a reaction by studying the oxidation-deprotonation reactions of a tungsten hydride complex. The rate dependence on the driving force for both electron transfer and proton transfer-employing different combinations of oxidants and bases-was used to establish experimentally the concerted, bidirectional PCET of a metal-hydride species. Consideration of the findings presented here in future catalyst designs may lead to more-efficient catalysts.
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| 9. |
- Brem, Jürgen, et al.
(author)
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Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors
- 2022
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In: Nature Chemistry. - : Springer Nature. - 1755-4330 .- 1755-4349. ; 14:1, s. 15-24
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Journal article (peer-reviewed)abstract
- Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.
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| 10. |
- Bräuer, Alois, et al.
(author)
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Structural snapshots of the minimal PKS system responsible for octaketide biosynthesis
- 2020
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In: Nature Chemistry. - : Springer Science and Business Media LLC. - 1755-4330 .- 1755-4349. ; 12:8
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Journal article (peer-reviewed)abstract
- The invariable core of a type II polyketide synthase has been characterized using X-ray crystallography, simulations, mutagenesis experiments and functional assays. The characterization of the ternary acyl carrier protein complexes provides a mechanistic understanding of the reactivity and could inform future engineering of this complex biosynthetic machinery. Type II polyketide synthases (PKSs) are multi-enzyme complexes that produce secondary metabolites of medical relevance. Chemical backbones of such polyketides are produced by minimal PKS systems that consist of a malonyl transacylase, an acyl carrier protein and an alpha/beta heterodimeric ketosynthase. Here, we present X-ray structures of all ternary complexes that constitute the minimal PKS system for anthraquinone biosynthesis inPhotorhabdus luminescens. In addition, we characterize this invariable core using molecular simulations, mutagenesis experiments and functional assays. We show that malonylation of the acyl carrier protein is accompanied by major structural rearrangements in the transacylase. Principles of an ongoing chain elongation are derived from the ternary complex with a hexaketide covalently linking the heterodimeric ketosynthase with the acyl carrier protein. Our results for the minimal PKS system provide mechanistic understanding of PKSs and a fundamental basis for engineering PKS pathways for future applications.
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