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Structural analysis of the N ‐acetyltransferase Eis1 from Mycobacterium abscessus reveals the molecular determinants of its incapacity to modify aminoglycosides

Abstract : Enhanced intracellular survival (Eis) proteins belonging to the superfamily of the GCN5-related N-acetyltransferases play important functions in mycobacterial pathogenesis. In Mycobacterium tuberculosis, Eis enhances the intracellular survival of the bacilli in macrophages by modulating the host immune response and is capable to chemically modify and inactivate aminoglycosides. In non-tuberculous mycobacteria (NTM), Eis shares similar functions. However, Mycobacterium abscessus, a multi-drug resistant NTM, possesses two functionally distinct Eis homologues, Eis1 Mab and Eis2 Mab. While Eis2 Mab participates in virulence and aminoglycosides resistance, this is not the case for Eis1 Mab, whose exact biological function remains to be determined. Herein, we show that overexpression of Eis1 Mab in M. abscessus fails to induce resistance to aminoglycosides. To clarify why Eis1 Mab is unable to modify this class of antibiotics, we solved its crystal structure bound to its cofactor, acetyl-CoA. The structure revealed that Eis1 Mab has a typical homohexameric Eis-like organization. The structural analysis supported by biochemical approaches demonstrated that while Eis1 Mab can acetylate small substrates, its active site is too narrow to accommodate aminoglycosides. Comparison with other Eis structures showed that an extended loop between strands 9 and 10 is blocking the access of large substrates to the active site and movement of helices 4 and 5 reduces the volume of the substrate-binding pocket to these compounds in Eis1 Mab. Overall, this study underscores the molecular determinants explaining functional differences between Eis1 Mab and Eis2 Mab, especially those inherent to their capacity to modify aminoglycosides.
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Contributor : Mickael Blaise Connect in order to contact the contributor
Submitted on : Thursday, November 5, 2020 - 4:32:56 PM
Last modification on : Tuesday, January 25, 2022 - 10:18:54 AM
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Kien Lam Ung, Laurent Kremer, Mickael Blaise. Structural analysis of the N ‐acetyltransferase Eis1 from Mycobacterium abscessus reveals the molecular determinants of its incapacity to modify aminoglycosides. Proteins - Structure, Function and Bioinformatics, Wiley, 2020, 89, pp.94 - 106. ⟨10.1002/prot.25997⟩. ⟨hal-02988304v2⟩



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