Conformational Selection and Induced Fit: The Behavior of Two Homologous Proteases
Abstract Protein‐ligand interactions are crucial for many cellular processes, with details of the binding mechanism being discussed as essential for biological functions. Interestingly, protein binding often involves conformational changes between two or more states, whereby different binding mechan...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley-VCH
2023-11-01
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| Series: | ChemistryEurope |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ceur.202300060 |
| _version_ | 1797449772925190144 |
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| author | Hannah Maus Gerald Hinze Stefan J. Hammerschmidt Prof. Dr. Tanja Schirmeister Prof. Dr. Thomas Basché |
| author_facet | Hannah Maus Gerald Hinze Stefan J. Hammerschmidt Prof. Dr. Tanja Schirmeister Prof. Dr. Thomas Basché |
| author_sort | Hannah Maus |
| collection | DOAJ |
| description | Abstract Protein‐ligand interactions are crucial for many cellular processes, with details of the binding mechanism being discussed as essential for biological functions. Interestingly, protein binding often involves conformational changes between two or more states, whereby different binding mechanisms are possible even with a simple two‐state description. Two models are widely used to portray protein‐ligand interactions: Induced fit and conformational selection. However, distinguishing them experimentally is challenging. Single‐molecule Förster resonance energy transfer (smFRET) has emerged as a powerful tool to resolve structural dynamics at the level of single proteins. Here, we investigated immobilized Zika virus (ZIKV) and dengue virus (DENV2) NS2B‐NS3 proteases using smFRET to compare their conformational changes upon binding to competitive small molecule inhibitors. The analysis of the smFRET data allowed us to distinguish between induced fit and conformational selection models and assign the binding mechanism from the kinetic parameters obtained. Although DENV and ZIKV protease are proteins with high structural similarities, our results reveal that they have opposite binding mechanisms for competitive ligands. While the protein‐ligand interaction in the ZIKV protease follows an induced fit mechanism, the DENV protease follows the conformational selection mechanism. |
| first_indexed | 2024-03-09T14:29:54Z |
| format | Article |
| id | doaj.art-8987fede8d8e45cdb04a81d2a0d9f1f7 |
| institution | Directory Open Access Journal |
| issn | 2751-4765 |
| language | English |
| last_indexed | 2024-03-09T14:29:54Z |
| publishDate | 2023-11-01 |
| publisher | Wiley-VCH |
| record_format | Article |
| series | ChemistryEurope |
| spelling | doaj.art-8987fede8d8e45cdb04a81d2a0d9f1f72023-11-28T02:09:21ZengWiley-VCHChemistryEurope2751-47652023-11-0113n/an/a10.1002/ceur.202300060Conformational Selection and Induced Fit: The Behavior of Two Homologous ProteasesHannah Maus0Gerald Hinze1Stefan J. Hammerschmidt2Prof. Dr. Tanja Schirmeister3Prof. Dr. Thomas Basché4Institute of Pharmaceutical and Biomedical Sciences (IPBS) Johannes Gutenberg-University Staudingerweg 5 55128 Mainz GermanyDepartment of Chemistry Johannes Gutenberg-University Johann-Joachim-Becher Weg-18-20 55128 Mainz GermanyInstitute of Pharmaceutical and Biomedical Sciences (IPBS) Johannes Gutenberg-University Staudingerweg 5 55128 Mainz GermanyInstitute of Pharmaceutical and Biomedical Sciences (IPBS) Johannes Gutenberg-University Staudingerweg 5 55128 Mainz GermanyDepartment of Chemistry Johannes Gutenberg-University Johann-Joachim-Becher Weg-18-20 55128 Mainz GermanyAbstract Protein‐ligand interactions are crucial for many cellular processes, with details of the binding mechanism being discussed as essential for biological functions. Interestingly, protein binding often involves conformational changes between two or more states, whereby different binding mechanisms are possible even with a simple two‐state description. Two models are widely used to portray protein‐ligand interactions: Induced fit and conformational selection. However, distinguishing them experimentally is challenging. Single‐molecule Förster resonance energy transfer (smFRET) has emerged as a powerful tool to resolve structural dynamics at the level of single proteins. Here, we investigated immobilized Zika virus (ZIKV) and dengue virus (DENV2) NS2B‐NS3 proteases using smFRET to compare their conformational changes upon binding to competitive small molecule inhibitors. The analysis of the smFRET data allowed us to distinguish between induced fit and conformational selection models and assign the binding mechanism from the kinetic parameters obtained. Although DENV and ZIKV protease are proteins with high structural similarities, our results reveal that they have opposite binding mechanisms for competitive ligands. While the protein‐ligand interaction in the ZIKV protease follows an induced fit mechanism, the DENV protease follows the conformational selection mechanism.https://doi.org/10.1002/ceur.202300060binding mechanism of competitive inhibitorsflaviviral proteasesmolecular dynamicsprotein foldingsmFRET |
| spellingShingle | Hannah Maus Gerald Hinze Stefan J. Hammerschmidt Prof. Dr. Tanja Schirmeister Prof. Dr. Thomas Basché Conformational Selection and Induced Fit: The Behavior of Two Homologous Proteases ChemistryEurope binding mechanism of competitive inhibitors flaviviral proteases molecular dynamics protein folding smFRET |
| title | Conformational Selection and Induced Fit: The Behavior of Two Homologous Proteases |
| title_full | Conformational Selection and Induced Fit: The Behavior of Two Homologous Proteases |
| title_fullStr | Conformational Selection and Induced Fit: The Behavior of Two Homologous Proteases |
| title_full_unstemmed | Conformational Selection and Induced Fit: The Behavior of Two Homologous Proteases |
| title_short | Conformational Selection and Induced Fit: The Behavior of Two Homologous Proteases |
| title_sort | conformational selection and induced fit the behavior of two homologous proteases |
| topic | binding mechanism of competitive inhibitors flaviviral proteases molecular dynamics protein folding smFRET |
| url | https://doi.org/10.1002/ceur.202300060 |
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