| 1. |
- Agback, Tatiana, et al.
(författare)
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Combined NMR and molecular dynamics conformational filter identifies unambiguously dynamic ensembles of Dengue protease NS2B/NS3pro
- 2023
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Ingår i: COMMUNICATIONS BIOLOGY. - 2399-3642. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- The dengue protease NS2B/NS3pro has been reported to adopt either an 'open' or a 'closed' conformation. We have developed a conformational filter that combines NMR with MD simulations to identify conformational ensembles that dominate in solution. Experimental values derived from relaxation parameters for the backbone and methyl side chains were compared with the corresponding back-calculated relaxation parameters of different conformational ensembles obtained from free MD simulations. Our results demonstrate a high prevalence for the 'closed' conformational ensemble while the 'open' conformation is absent, indicating that the latter conformation is most probably due to crystal contacts. Conversely, conformational ensembles in which the positioning of the co-factor NS2B results in a 'partially' open conformation, previously described in both MD simulations and X-ray studies, were identified by our conformational filter. Altogether, we believe that our approach allows for unambiguous identification of true conformational ensembles, an essential step for reliable drug discovery. A conformational filter that combines NMR with MD simulations to identify conformational ensembles that dominate in solution suggests dengue protease NS2B/NS3pro predominantly exists in a "closed" conformation.
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| 2. |
- Wallerstein, Johan, et al.
(författare)
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Insights into mechanisms of MALT1 allostery from NMR and AlphaFold dynamic analyses
- 2024
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Ingår i: Communications Biology. - : NATURE PORTFOLIO. - 2399-3642. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Mucosa-associated lymphoid tissue lymphoma-translocation protein 1 (MALT1) is an attractive target for the development of modulatory compounds in the treatment of lymphoma and other cancers. While the three-dimensional structure of MALT1 has been previously determined through X-ray analysis, its dynamic behaviour in solution has remained unexplored. We present here dynamic analyses of the apo MALT1 form along with the E549A mutation. This investigation used NMR 15N relaxation and NOE measurements between side-chain methyl groups. Our findings confirm that MALT1 exists as a monomer in solution, and demonstrate that the domains display semi-independent movements in relation to each other. Our dynamic study, covering multiple time scales, along with the assessment of conformational populations by Molecular Dynamic simulations, Alpha Fold modelling and PCA analysis, put the side chain of residue W580 in an inward position, shedding light at potential mechanisms underlying the allosteric regulation of this enzyme. NMR relaxation and AlphaFold structural ensemble modelling of MALT1 reveals motions between its PCASP and Ig3 domains. This sheds light into the mechanisms of the protein's allosteric regulation.
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| 3. |
- Wallerstein, Johan, 1978, et al.
(författare)
-
Insights into mechanisms of MALT1 allostery from NMR and AlphaFold dynamic analyses
- 2024
-
Ingår i: COMMUNICATIONS BIOLOGY. - : NATURE PORTFOLIO. - 2399-3642. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- Mucosa-associated lymphoid tissue lymphoma-translocation protein 1 (MALT1) is an attractive target for the development of modulatory compounds in the treatment of lymphoma and other cancers. While the three-dimensional structure of MALT1 has been previously determined through X-ray analysis, its dynamic behaviour in solution has remained unexplored. We present here dynamic analyses of the apo MALT1 form along with the E549A mutation. This investigation used NMR 15N relaxation and NOE measurements between side-chain methyl groups. Our findings confirm that MALT1 exists as a monomer in solution, and demonstrate that the domains display semi-independent movements in relation to each other. Our dynamic study, covering multiple time scales, along with the assessment of conformational populations by Molecular Dynamic simulations, Alpha Fold modelling and PCA analysis, put the side chain of residue W580 in an inward position, shedding light at potential mechanisms underlying the allosteric regulation of this enzyme. NMR relaxation and AlphaFold structural ensemble modelling of MALT1 reveals motions between its PCASP and Ig3 domains. This sheds light into the mechanisms of the protein's allosteric regulation.
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