Aspectos estructurales y funcionales de la N-Succinil-L, L-diaminopimelato desuccinilasa, una enzima clave para el crecimiento bacteriano y un blanco para el control antimicrobiano

Díaz‐Sánchez, Ángel G.; Terrazas-López, Manuel; Aguirre-Reyes, Luis Guadalupe; Lobo, Neethan A.; ́Álvarez-Parrilla, Emilio; Martínez‐Martínez, Alejandro

doi:10.22201/fesz.23958723e.2019.0.191

Cited by 3 publications

(2 citation statements)

References 76 publications

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“…Comparison of three different DapE crystal structures (PDB entries 5UEJ, 5VO3, and 3IC1) reveals significant differences in the orientations of the domains (Figure 2C−E). The dramatic change from the open to the closed conformation has been noted previously; 12,36 however, even the differences in conformations of available open structures (PDB entries 3IC1 and 5UEJ) are striking, and comparison of eight different DapE structures (Figure S2) underscores the wide range of conformational flexibility of the DapE subunits. The product-bound structure manifests a twist (Figure 2C) different from that of the structures without product, and we have analyzed this change using conformationally sensitive dihedral angles (Figures S1 and S2).…”

Section: ■ Experimental Sectionsupporting

confidence: 64%

Atomic-Resolution 1.3 Å Crystal Structure, Inhibition by Sulfate, and Molecular Dynamics of the Bacterial Enzyme DapE

et al. 2021

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We report the atomic-resolution (1.3 Å) X-ray crystal structure of an open conformation of the dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE, EC 3.5.1.18) from Neisseria meningitidis. This structure [Protein Data Bank (PDB) entry 5UEJ] contains two bound sulfate ions in the active site that mimic the binding of the terminal carboxylates of the N-succinyl-l,l-diaminopimelic acid (l,l-SDAP) substrate. We demonstrated inhibition of DapE by sulfate (IC50 = 13.8 ± 2.8 mM). Comparison with other DapE structures in the PDB demonstrates the flexibility of the interdomain connections of this protein. This high-resolution structure was then utilized as the starting point for targeted molecular dynamics experiments revealing the conformational change from the open form to the closed form that occurs when DapE binds l,l-SDAP and cleaves the amide bond. These simulations demonstrated closure from the open to the closed conformation, the change in RMS throughout the closure, and the independence in the movement of the two DapE subunits. This conformational change occurred in two phases with the catalytic domains moving toward the dimerization domains first, followed by a rotation of catalytic domains relative to the dimerization domains. Although there were no targeting forces, the substrate moved closer to the active site and bound more tightly during the closure event.

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Section: ■ Experimental Sectionsupporting

confidence: 64%

Atomic-Resolution 1.3 Å Crystal Structure, Inhibition by Sulfate, and Molecular Dynamics of the Bacterial Enzyme DapE

et al. 2021

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“…In contrast, alignment of the hinge regions of open and closed structures demonstrates the flexibility of this region, suggesting that changes in quaternary structure are determined by movements in the hinge region rather than changes in the structures of other domains (Figure D). These overlays complement the analyses of DapE performed by Díaz-Sánchez …”

Section: Resultsmentioning

confidence: 99%

Biochemical and Structural Analysis of the Bacterial Enzyme Succinyl-Diaminopimelate Desuccinylase (DapE) from Acinetobacter baumannii

Kelley,

Minasov,

Konczak

et al. 2024

ACS Omega

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There is an urgent need for new antibiotics given the rise of antibiotic resistance, and succinyl-diaminopimelate desuccinylase (DapE, E.C. 3.5.1.18) has emerged as a promising bacterial enzyme target. DapE from Haemophilus influenzae (HiDapE) has been studied and inhibitors identified, but it is essential to explore DapE from different species to assess selective versus broad-spectrum therapeutics. We have determined the structure of DapE from the ESKAPE pathogen Acinetobacter baumannii (AbDapE) and studied inhibition by known inhibitors of HiDapE. AbDapE is inhibited by captopril and sulfate comparable to HiDapE, but AbDapE was not significantly inhibited by a known indoline sulfonamide HiDapE inhibitor. Captopril and sulfate both stabilize HiDapE by increasing the thermal melting temperature (T m ) in thermal shift assays. By contrast, sulfate decreases the stability of the AbDapE enzyme, whereas captopril increases the stability. Further, we report two crystal structures of selenomethionine-substituted AbDapE in the closed conformation, one with AbDapE in complex with succinate derived from enzymatic hydrolysis of N 6 -methyl-L,L-SDAP substrate and acetate (PDB code 7T1Q, 2.25 Å resolution), and a crystal structure of AbDapE with bound succinate along with L-(S)-lactate, a product of degradation of citric acid from the crystallization buffer during X-ray irradiation (PDB code 8F8O, 2.10 Å resolution).

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The three-dimensional structure of DapE from Enterococcus faecium reveals new insights into DapE/ArgE subfamily ligand specificity

Terrazas-López,

González-Segura,

Díaz-Vilchis

et al. 2024

International Journal of Biological Macromolecules

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Aspectos estructurales y funcionales de la N-Succinil-L, L-diaminopimelato desuccinilasa, una enzima clave para el crecimiento bacteriano y un blanco para el control antimicrobiano

Cited by 3 publications

References 76 publications

Atomic-Resolution 1.3 Å Crystal Structure, Inhibition by Sulfate, and Molecular Dynamics of the Bacterial Enzyme DapE

Atomic-Resolution 1.3 Å Crystal Structure, Inhibition by Sulfate, and Molecular Dynamics of the Bacterial Enzyme DapE

Biochemical and Structural Analysis of the Bacterial Enzyme Succinyl-Diaminopimelate Desuccinylase (DapE) from Acinetobacter baumannii

The three-dimensional structure of DapE from Enterococcus faecium reveals new insights into DapE/ArgE subfamily ligand specificity

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