Mechanism-based and computational modeling of hydrogen sulfide biogenesis inhibition: interfacial inhibition
Abstract Hydrogen sulfide (H2S) is a gaseous signaling molecule that participates in various signaling functions in health and diseases. The tetrameric cystathionine γ-lyase (CSE) contributes to H2S biogenesis and several investigations provide evidence on the pharmacological modulation of CSE as a...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-34405-3 |
| _version_ | 1797832197168693248 |
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| author | Laurent Le Corre Dominique Padovani |
| author_facet | Laurent Le Corre Dominique Padovani |
| author_sort | Laurent Le Corre |
| collection | DOAJ |
| description | Abstract Hydrogen sulfide (H2S) is a gaseous signaling molecule that participates in various signaling functions in health and diseases. The tetrameric cystathionine γ-lyase (CSE) contributes to H2S biogenesis and several investigations provide evidence on the pharmacological modulation of CSE as a potential target for the treatment of a multitude of conditions. D-penicillamine (D-pen) has recently been reported to selectively impede CSE-catalyzed H2S production but the molecular bases for such inhibitory effect have not been investigated. In this study, we report that D-pen follows a mixed-inhibition mechanism to inhibit both cystathionine (CST) cleavage and H2S biogenesis by human CSE. To decipher the molecular mechanisms underlying such a mixed inhibition, we performed docking and molecular dynamics (MD) simulations. Interestingly, MD analysis of CST binding reveals a likely active site configuration prior to gem-diamine intermediate formation, particularly H-bond formation between the amino group of the substrate and the O3′ of PLP. Similar analyses realized with both CST and D-pen identified three potent interfacial ligand-binding sites for D-pen and offered a rational for D-pen effect. Thus, inhibitor binding not only induces the creation of an entirely new interacting network at the vicinity of the interface between enzyme subunits, but it also exerts long range effects by propagating to the active site. Overall, our study paves the way for the design of new allosteric interfacial inhibitory compounds that will specifically modulate H2S biogenesis by cystathionine γ-lyase. |
| first_indexed | 2024-04-09T14:03:56Z |
| format | Article |
| id | doaj.art-fbbfdb21839c4d098e3b6912d706ec42 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-09T14:03:56Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-fbbfdb21839c4d098e3b6912d706ec422023-05-07T11:10:56ZengNature PortfolioScientific Reports2045-23222023-05-0113111710.1038/s41598-023-34405-3Mechanism-based and computational modeling of hydrogen sulfide biogenesis inhibition: interfacial inhibitionLaurent Le Corre0Dominique Padovani1Université Paris Cité, CNRS, Laboratoire de Chimie et de Biochimie Pharmacologiques et ToxicologiquesUniversité Paris Cité, CNRS, Laboratoire de Chimie et de Biochimie Pharmacologiques et ToxicologiquesAbstract Hydrogen sulfide (H2S) is a gaseous signaling molecule that participates in various signaling functions in health and diseases. The tetrameric cystathionine γ-lyase (CSE) contributes to H2S biogenesis and several investigations provide evidence on the pharmacological modulation of CSE as a potential target for the treatment of a multitude of conditions. D-penicillamine (D-pen) has recently been reported to selectively impede CSE-catalyzed H2S production but the molecular bases for such inhibitory effect have not been investigated. In this study, we report that D-pen follows a mixed-inhibition mechanism to inhibit both cystathionine (CST) cleavage and H2S biogenesis by human CSE. To decipher the molecular mechanisms underlying such a mixed inhibition, we performed docking and molecular dynamics (MD) simulations. Interestingly, MD analysis of CST binding reveals a likely active site configuration prior to gem-diamine intermediate formation, particularly H-bond formation between the amino group of the substrate and the O3′ of PLP. Similar analyses realized with both CST and D-pen identified three potent interfacial ligand-binding sites for D-pen and offered a rational for D-pen effect. Thus, inhibitor binding not only induces the creation of an entirely new interacting network at the vicinity of the interface between enzyme subunits, but it also exerts long range effects by propagating to the active site. Overall, our study paves the way for the design of new allosteric interfacial inhibitory compounds that will specifically modulate H2S biogenesis by cystathionine γ-lyase.https://doi.org/10.1038/s41598-023-34405-3 |
| spellingShingle | Laurent Le Corre Dominique Padovani Mechanism-based and computational modeling of hydrogen sulfide biogenesis inhibition: interfacial inhibition Scientific Reports |
| title | Mechanism-based and computational modeling of hydrogen sulfide biogenesis inhibition: interfacial inhibition |
| title_full | Mechanism-based and computational modeling of hydrogen sulfide biogenesis inhibition: interfacial inhibition |
| title_fullStr | Mechanism-based and computational modeling of hydrogen sulfide biogenesis inhibition: interfacial inhibition |
| title_full_unstemmed | Mechanism-based and computational modeling of hydrogen sulfide biogenesis inhibition: interfacial inhibition |
| title_short | Mechanism-based and computational modeling of hydrogen sulfide biogenesis inhibition: interfacial inhibition |
| title_sort | mechanism based and computational modeling of hydrogen sulfide biogenesis inhibition interfacial inhibition |
| url | https://doi.org/10.1038/s41598-023-34405-3 |
| work_keys_str_mv | AT laurentlecorre mechanismbasedandcomputationalmodelingofhydrogensulfidebiogenesisinhibitioninterfacialinhibition AT dominiquepadovani mechanismbasedandcomputationalmodelingofhydrogensulfidebiogenesisinhibitioninterfacialinhibition |