9PXS
Crystal Structure of Staphylococcus aureus D-alanine aminotransferase in complex with pyridoxal 5'-phosphate
Summary for 9PXS
| Entry DOI | 10.2210/pdb9pxs/pdb |
| Descriptor | D-alanine aminotransferase (1 entity in total) |
| Functional Keywords | aminotrasnferase, plp, cell wall biosynthesis, d-alanine, transferase |
| Biological source | Staphylococcus aureus |
| Total number of polymer chains | 1 |
| Total formula weight | 32170.89 |
| Authors | |
| Primary citation | Roy, R.,Jayasinghe, Y.P.,Panda, S.,Zeden, M.S.,Thomas, V.C.,Ronning, D.R.,O'Gara, J.P. A S 180 F substitution in D-alanine aminotransferase confers resistance to beta-chloro-D-alanine in Staphylococcus aureus. J.Biol.Chem., 301:110931-110931, 2025 Cited by PubMed Abstract: β-lactam antibiotics that target the synthesis of bacterial cell wall peptidoglycan (PG) remain a cornerstone of antimicrobial chemotherapy. The activity of β-lactams against methicillin-resistant Staphylococcus aureus (MRSA) can be enhanced by the alanine analog d-cycloserine (DCS), which blocks alanine racemase (Alr1) and d-alanine ligase (Ddl) and interferes with the supply of d-alanine for PG synthesis. Here, we report that another alanine analogue antibiotic, β-chloro-d-alanine (BCDA), also interferes with the d-alanine pathway by targeting d-alanine aminotransferase (Dat), which converts pyruvate to d-alanine. A Dat SF substitution, identified in a BCDA resistant MRSA mutant, resulted in reduced transaminase activity. X-ray crystallographic analysis of S. aureus Dat allowed structural modeling of the Dat-SF variant, which revealed an active-site loop shift that altered PLP co-factor binding. Molecular docking analysis suggests that the SF substitution promotes BCDA-PLP adduct dissociation via a mechanism that releases inactivated BCDA, thereby conferring resistance. These findings reveal a novel mechanism of BCDA resistance in S. aureus and the therapeutic potential of targeting Alr1 and Dat with DCS and BCDA, respectively, as part of an alternative treatment strategy for MRSA infections. PubMed: 41232672DOI: 10.1016/j.jbc.2025.110931 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.94 Å) |
Structure validation
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