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| 2. |
- Noske, G. D., et al.
(författare)
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A Crystallographic Snapshot of SARS-CoV-2 Main Protease Maturation Process : SARS-CoV-2 Mpro maturation
- 2021
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836. ; 433:18
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Tidskriftsartikel (refereegranskat)abstract
- SARS-CoV-2 is the causative agent of COVID-19. The dimeric form of the viral Mpro is responsible for the cleavage of the viral polyprotein in 11 sites, including its own N and C-terminus. The lack of structural information for intermediary forms of Mpro is a setback for the understanding its self-maturation process. Herein, we used X-ray crystallography combined with biochemical data to characterize multiple forms of SARS-CoV-2 Mpro. For the immature form, we show that extra N-terminal residues caused conformational changes in the positioning of domain-three over the active site, hampering the dimerization and diminishing its activity. We propose that this form preludes the cis and trans-cleavage of N-terminal residues. Using fragment screening, we probe new cavities in this form which can be used to guide therapeutic development. Furthermore, we characterized a serine site-directed mutant of the Mpro bound to its endogenous N and C-terminal residues during dimeric association stage of the maturation process. We suggest this form is a transitional state during the C-terminal trans-cleavage. This data sheds light in the structural modifications of the SARS-CoV-2 main protease during its self-maturation process.
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| 3. |
- Muller, S, et al.
(författare)
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Target 2035 - update on the quest for a probe for every protein
- 2022
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Ingår i: RSC medicinal chemistry. - : Royal Society of Chemistry (RSC). - 2632-8682. ; 13:1, s. 13-21
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. Target 2035 aims to develop a pharmacological modulator for every protein in the human proteome to fill this gap.
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| 4. |
- Von Delft, A, et al.
(författare)
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Why healthcare workers are sick of TB
- 2015
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Ingår i: International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. - : Elsevier BV. - 1878-3511. ; 32, s. 147-151
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Godoy, Andre Schutzer, et al.
(författare)
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Allosteric regulation and crystallographic fragment screening of SARS-CoV-2 NSP15 endoribonuclease
- 2023
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Ingår i: Nucleic Acids Research. - 0305-1048. ; 51:10, s. 5255-5270
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Tidskriftsartikel (refereegranskat)abstract
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The NSP15 endoribonuclease enzyme, known as NendoU, is highly conserved and plays a critical role in the ability of the virus to evade the immune system. NendoU is a promising target for the development of new antiviral drugs. However, the complexity of the enzyme's structure and kinetics, along with the broad range of recognition sequences and lack of structural complexes, hampers the development of inhibitors. Here, we performed enzymatic characterization of NendoU in its monomeric and hexameric form, showing that hexamers are allosteric enzymes with a positive cooperative index, and with no influence of manganese on enzymatic activity. Through combining cryo-electron microscopy at different pHs, X-ray crystallography and biochemical and structural analysis, we showed that NendoU can shift between open and closed forms, which probably correspond to active and inactive states, respectively. We also explored the possibility of NendoU assembling into larger supramolecular structures and proposed a mechanism for allosteric regulation. In addition, we conducted a large fragment screening campaign against NendoU and identified several new allosteric sites that could be targeted for the development of new inhibitors. Overall, our findings provide insights into the complex structure and function of NendoU and offer new opportunities for the development of inhibitors.
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