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Unraveling the mechanism of small molecule induced activation of Staphylococcus aureus signal peptidase IB.
Chen, Shu-Yu; Fiedler, Michaela K; Gronauer, Thomas F; Omelko, Olesia; von Wrisberg, Marie-Kristin; Wang, Tao; Schneider, Sabine; Sieber, Stephan A; Zacharias, Martin.
Afiliación
  • Chen SY; Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 2, Zurich, 8093, Switzerland.
  • Fiedler MK; TUM School of Natural Sciences, Department Biosciences, Theoretical Biophysics (T38), Center for Functional Protein Assemblies (CPA), Technical University Munich (TUM), Ernst-Otto-Fischer Str. 8, Garching, 85748, Germany.
  • Gronauer TF; TUM School of Natural Sciences, Department Biosciences, Chair of Organic Chemistry II, Center for Functional Protein Assemblies (CPA), Technical University Munich (TUM), Ernst-Otto-Fischer Str. 8, Garching, 85748, Germany.
  • Omelko O; TUM School of Natural Sciences, Department Biosciences, Chair of Organic Chemistry II, Center for Functional Protein Assemblies (CPA), Technical University Munich (TUM), Ernst-Otto-Fischer Str. 8, Garching, 85748, Germany.
  • von Wrisberg MK; TUM School of Natural Sciences, Department Biosciences, Chair of Organic Chemistry II, Center for Functional Protein Assemblies (CPA), Technical University Munich (TUM), Ernst-Otto-Fischer Str. 8, Garching, 85748, Germany.
  • Wang T; Department of Chemistry, Ludwig-Maximilians University Munich (LMU), Butenandtstr. 5-13, Munich, 81377, Germany.
  • Schneider S; TUM School of Natural Sciences, Department Biosciences, Chair of Organic Chemistry II, Center for Functional Protein Assemblies (CPA), Technical University Munich (TUM), Ernst-Otto-Fischer Str. 8, Garching, 85748, Germany.
  • Sieber SA; Department of Chemistry, Ludwig-Maximilians University Munich (LMU), Butenandtstr. 5-13, Munich, 81377, Germany.
  • Zacharias M; TUM School of Natural Sciences, Department Biosciences, Chair of Organic Chemistry II, Center for Functional Protein Assemblies (CPA), Technical University Munich (TUM), Ernst-Otto-Fischer Str. 8, Garching, 85748, Germany. stephan.sieber@tum.de.
Commun Biol ; 7(1): 895, 2024 Jul 24.
Article en En | MEDLINE | ID: mdl-39043865
ABSTRACT
Staphylococcus aureus signal peptidase IB (SpsB) is an essential enzyme for protein secretion. While inhibition of its activity by small molecules is a well-precedented mechanism to kill bacteria, the mode of activation is however less understood. We here investigate the activation mechanism of a recently introduced activator, the antibiotic compound PK150, and demonstrate by combined experimental and Molecular Dynamics (MD) simulation studies a unique principle of enzyme stimulation. Mass spectrometric studies with an affinity-based probe of PK150 unravel the binding site of PK150 in SpsB which is used as a starting point for MD simulations. Our model shows the localization of the molecule in an allosteric pocket next to the active site which shields the catalytic dyad from excess water that destabilizes the catalytic geometry. This mechanism is validated by the placement of mutations aligning the binding pocket of PK150. While the mutants retain turnover of the SpsB substrate, no stimulation of activity is observed upon PK150 addition. Overall, our study elucidates a previously little investigated mechanism of enzyme activation and serves as a starting point for the development of future enzyme activators.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Staphylococcus aureus / Proteínas Bacterianas / Serina Endopeptidasas / Simulación de Dinámica Molecular Idioma: En Revista: Commun Biol Año: 2024 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Reino Unido
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Staphylococcus aureus / Proteínas Bacterianas / Serina Endopeptidasas / Simulación de Dinámica Molecular Idioma: En Revista: Commun Biol Año: 2024 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Reino Unido