7S0V
The role of an Asp-Asp pair in the structure, function and inhibition of CTX-M Class A Beta-lactamase
Summary for 7S0V
| Entry DOI | 10.2210/pdb7s0v/pdb |
| Descriptor | Beta-lactamase, 3-(1H-pyrazol-1-yl)-N-[3-(1H-tetrazol-5-yl)phenyl]-5-(trifluoromethyl)benzamide (3 entities in total) |
| Functional Keywords | inhibitor, complex, asp-asp, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Escherichia coli |
| Total number of polymer chains | 1 |
| Total formula weight | 28398.89 |
| Authors | Kemp, M.T.,Chen, Y. (deposition date: 2021-08-31, release date: 2021-11-10, Last modification date: 2024-05-22) |
| Primary citation | Kemp, M.T.,Nichols, D.A.,Zhang, X.,Defrees, K.,Na, I.,Renslo, A.R.,Chen, Y. Mutation of the conserved Asp-Asp pair impairs the structure, function, and inhibition of CTX-M Class A beta-lactamase. Febs Lett., 595:2981-2994, 2021 Cited by PubMed Abstract: The Asp233-Asp246 pair is highly conserved in Class A β-lactamases, which hydrolyze β-lactam antibiotics. Here, we characterize its function using CTX-M-14 β-lactamase. The D233N mutant displayed decreased activity that is substrate-dependent, with reductions in k /K ranging from 20% for nitrocefin to 6-fold for cefotaxime. In comparison, the mutation reduced the binding of a known reversible inhibitor by 10-fold. The mutant structures showed movement of the 213-219 loop and the loss of the Thr216-Thr235 hydrogen bond, which was restored by inhibitor binding. Mutagenesis of Thr216 further highlighted its contribution to CTX-M activity. These results demonstrate the importance of the aspartate pair to CTX-M hydrolysis of substrates with bulky side chains, while suggesting increased protein flexibility as a means to evolve drug resistance. PubMed: 34704263DOI: 10.1002/1873-3468.14215 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
Download full validation report
