5JNM
Crystal structure of MtlD from Staphylococcus aureus at 1.7-Angstrom resolution
Summary for 5JNM
| Entry DOI | 10.2210/pdb5jnm/pdb |
| Descriptor | Mannitol-1-phosphate 5-dehydrogenase, SULFATE ION (3 entities in total) |
| Functional Keywords | mannitol-1-phosphate fructose-6-phosphate nad dehydrogenase, oxidoreductase |
| Biological source | Staphylococcus aureus (strain Mu3 / ATCC 700698) |
| Total number of polymer chains | 1 |
| Total formula weight | 45210.73 |
| Authors | Ta, H.M.,Nguyen, T.,Kim, T.,Kim, K.K. (deposition date: 2016-04-30, release date: 2017-11-08, Last modification date: 2024-10-23) |
| Primary citation | Nguyen, T.,Kim, T.,Ta, H.M.,Yeo, W.S.,Choi, J.,Mizar, P.,Lee, S.S.,Bae, T.,Chaurasia, A.K.,Kim, K.K. Targeting Mannitol Metabolism as an Alternative Antimicrobial Strategy Based on the Structure-Function Study of Mannitol-1-Phosphate Dehydrogenase in Staphylococcus aureus. Mbio, 10:-, 2019 Cited by PubMed Abstract: Mannitol-1-phosphate dehydrogenase (M1PDH) is a key enzyme in mannitol metabolism, but its roles in pathophysiological settings have not been established. We performed comprehensive structure-function analysis of M1PDH from USA300, a strain of community-associated methicillin-resistant , to evaluate its roles in cell viability and virulence under pathophysiological conditions. On the basis of our results, we propose M1PDH as a potential antibacterial target. cell viability assessment of Δ knockout and complemented strains confirmed that M1PDH is essential to endure pH, high-salt, and oxidative stress and thus that M1PDH is required for preventing osmotic burst by regulating pressure potential imposed by mannitol. The mouse infection model also verified that M1PDH is essential for bacterial survival during infection. To further support the use of M1PDH as an antibacterial target, we identified dihydrocelastrol (DHCL) as a competitive inhibitor of M1PDH (M1PDH) and confirmed that DHCL effectively reduces bacterial cell viability during host infection. To explain physiological functions of M1PDH at the atomic level, the crystal structure of M1PDH was determined at 1.7-Å resolution. Structure-based mutation analyses and DHCL molecular docking to the M1PDH active site followed by functional assay identified key residues in the active site and provided the action mechanism of DHCL. Collectively, we propose M1PDH as a target for antibiotic development based on its physiological roles with the goals of expanding the repertory of antibiotic targets to fight antimicrobial resistance and providing essential knowledge for developing potent inhibitors of M1PDH based on structure-function studies. Due to the shortage of effective antibiotics against drug-resistant , new targets are urgently required to develop next-generation antibiotics. We investigated mannitol-1-phosphate dehydrogenase of USA300 (M1PDH), a key enzyme regulating intracellular mannitol levels, and explored the possibility of using M1PDH as a target for developing antibiotic. Since mannitol is necessary for maintaining the cellular redox and osmotic potential, the homeostatic imbalance caused by treatment with a M1PDH inhibitor or knockout of the gene encoding M1PDH results in bacterial cell death through oxidative and/or mannitol-dependent cytolysis. We elucidated the molecular mechanism of M1PDH and the structural basis of substrate and inhibitor recognition by enzymatic and structural analyses of M1PDH. Our results strongly support the concept that targeting of M1PDH represents an alternative strategy for developing a new class of antibiotics that cause bacterial cell death not by blocking key cellular machinery but by inducing cytolysis and reducing stress tolerance through inhibition of the mannitol pathway. PubMed: 31289190DOI: 10.1128/mBio.02660-18 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.701 Å) |
Structure validation
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