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dc.contributor.author
Nicoll, Callum R.  
dc.contributor.author
Bailleul, Gautier  
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Fiorentini, Filippo  
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Mascotti, María Laura  
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Fraaije, Marco Wilhelmus  
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Mattevi, Andrea  
dc.date.available
2021-10-26T10:51:18Z  
dc.date.issued
2020-01  
dc.identifier.citation
Nicoll, Callum R.; Bailleul, Gautier; Fiorentini, Filippo; Mascotti, María Laura; Fraaije, Marco Wilhelmus; et al.; Ancestral-sequence reconstruction unveils the structural basis of function in mammalian FMOs; Nature; Nature Structural and Molecular Biology; 27; 1; 1-2020; 14-24  
dc.identifier.issn
1545-9993  
dc.identifier.uri
http://hdl.handle.net/11336/145009  
dc.description.abstract
Flavin-containing monooxygenases (FMOs) are ubiquitous in all domains of life and metabolize a myriad of xenobiotics, including toxins, pesticides and drugs. However, despite their pharmacological importance, structural information remains bereft. To further our understanding behind their biochemistry and diversity, we used ancestral-sequence reconstruction, kinetic and crystallographic techniques to scrutinize three ancient mammalian FMOs: AncFMO2, AncFMO3-6 and AncFMO5. Remarkably, all AncFMOs could be crystallized and were structurally resolved between 2.7- and 3.2-Å resolution. These crystal structures depict the unprecedented topology of mammalian FMOs. Each employs extensive membrane-binding features and intricate substrate-profiling tunnel networks through a conspicuous membrane-adhering insertion. Furthermore, a glutamate–histidine switch is speculated to induce the distinctive Baeyer–Villiger oxidation activity of FMO5. The AncFMOs exhibited catalysis akin to human FMOs and, with sequence identities between 82% and 92%, represent excellent models. Our study demonstrates the power of ancestral-sequence reconstruction as a strategy for the crystallization of proteins.  
dc.format
application/pdf  
dc.language.iso
eng  
dc.publisher
Nature  
dc.rights
info:eu-repo/semantics/restrictedAccess  
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/  
dc.subject
ENZYMES  
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ENZYME MECHANISMS  
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EVOLUTION  
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STRUCTURE DETERMINATION  
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X-RAY CRYSTALLOGRAPHY  
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Bioquímica y Biología Molecular  
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Ciencias Biológicas  
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CIENCIAS NATURALES Y EXACTAS  
dc.title
Ancestral-sequence reconstruction unveils the structural basis of function in mammalian FMOs  
dc.type
info:eu-repo/semantics/article  
dc.type
info:ar-repo/semantics/artículo  
dc.type
info:eu-repo/semantics/publishedVersion  
dc.date.updated
2021-09-07T13:57:13Z  
dc.identifier.eissn
1545-9985  
dc.journal.volume
27  
dc.journal.number
1  
dc.journal.pagination
14-24  
dc.journal.pais
Estados Unidos  
dc.description.fil
Fil: Nicoll, Callum R.. Universita Degli Studi Di Pavia; Italia  
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Fil: Bailleul, Gautier. University of Groningen; Países Bajos  
dc.description.fil
Fil: Fiorentini, Filippo. Universita Degli Studi Di Pavia; Italia  
dc.description.fil
Fil: Mascotti, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina  
dc.description.fil
Fil: Fraaije, Marco Wilhelmus. University Of Groningen. Faculty Of Science And Engineering. Engineering And Technology Institute Groningen.; Países Bajos  
dc.description.fil
Fil: Mattevi, Andrea. Universita Degli Studi Di Pavia; Italia  
dc.journal.title
Nature Structural and Molecular Biology  
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1038/s41594-019-0347-2