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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Energy landscape of the domain movement in Staphylococcus aureus UDP-N-acetylglucosamine 2-epimerase

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de Azevedo, Erika Chang [1] ; Nascimento, Alessandro S. [1]
Total Authors: 2
[1] Univ Sao Paulo, Inst Fis Sao Carlos, Av Trabalhador Saocarlense 400, BR-13566590 Sao Carlos, SP - Brazil
Total Affiliations: 1
Document type: Journal article
Source: Journal of Structural Biology; v. 207, n. 2, p. 158-168, AUG 1 2019.
Web of Science Citations: 0

Staphylococcus aureus is an important cause of resistant healthcare-associated infections. It has been shown that the wall teichoic acid (WTA) may be an important drug target acting on antibiotic-resistant cells. The UDP-N-acetylglucosamine 2-epimerase, MnaA, is one of the first enzymes on the pathway for the biosynthesis of the WTA. Here, detailed molecular dynamics simulations of S. aureus MnaA were used to characterize the conformational changes that occur in the presence of UDP and UDP-GlcNac and also the energetic landscape associated with these changes. Using different simulation techniques, such as ABMD and GAMD, it was possible to assess the energetic profile for the protein with and without ligands in its active site. We found that there is a dynamic energy landscape that has its minimum changed by the presence of the ligands, with a closed structure of the enzyme being more frequently observed for the bound state while the unbound enzyme favors an opened conformation. Further structural analysis indicated that positively charged amino acids associated with UDP and UDP-GlcNac interactions play a major role in the enzyme opening movement. Finally, the energy landscape profiled in this work provides important conclusions for the design of inhibitor candidates targeting S. aureus MnaA. (AU)

FAPESP's process: 15/13684-0 - Structural and functional studies of enzymes that participate in complex carbohydrates synthesis and degradation
Grantee:Igor Polikarpov
Support type: Research Projects - Thematic Grants
FAPESP's process: 17/18173-0 - Mechanisms Involved in Resistance to Antibiotics: Wall Teichoic Acids and Biofilms as Molecular Targets
Grantee:Alessandro Silva Nascimento
Support type: Regular Research Grants
FAPESP's process: 15/26722-8 - Drug discovery against human infectious diseases
Grantee:Carsten Wrenger
Support type: Research Projects - Thematic Grants