3ZCZ
Crystal structure of a complex between Actinomadura R39 DD-peptidase and a trifluoroketone inhibitor
Summary for 3ZCZ
| Entry DOI | 10.2210/pdb3zcz/pdb |
| Descriptor | D-ALANYL-D-ALANINE CARBOXYPEPTIDASE, (2R)-2-amino-7-oxo-7-{[(2R,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl]amino}heptanoic acid, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | hydrolase, inhibitor, peptidoglycan |
| Biological source | ACTINOMADURA SP. R39 |
| Cellular location | Secreted: P39045 |
| Total number of polymer chains | 4 |
| Total formula weight | 193843.67 |
| Authors | Sauvage, E.,Herman, R.,Kerff, F.,Rocaboy, M.,Charlier, P. (deposition date: 2012-11-23, release date: 2013-03-27, Last modification date: 2024-11-13) |
| Primary citation | Dzhekieva, L.,Adediran, S.A.,Herman, R.,Kerff, F.,Duez, C.,Charlier, P.,Sauvage, E.,Pratt, R.F. Inhibition of Dd-Peptidases by a Specific Trifluoroketone: Crystal Structure of a Complex with the Actinomadura R39 Dd-Peptidase. Biochemistry, 52:2128-, 2013 Cited by PubMed Abstract: Inhibitors of bacterial DD-peptidases represent potential antibiotics. In the search for alternatives to β-lactams, we have investigated a series of compounds designed to generate transition state analogue structures upon reaction with DD-peptidases. The compounds contain a combination of a peptidoglycan-mimetic specificity handle and a warhead capable of delivering a tetrahedral anion to the enzyme active site. The latter includes a boronic acid, two alcohols, an aldehyde, and a trifluoroketone. The compounds were tested against two low-molecular mass class C DD-peptidases. As expected from previous observations, the boronic acid was a potent inhibitor, but rather unexpectedly from precedent, the trifluoroketone [D-α-aminopimelyl(1,1,1-trifluoro-3-amino)butan-2-one] was also very effective. Taking into account competing hydration, we found the trifluoroketone was the strongest inhibitor of the Actinomadura R39 DD-peptidase, with a subnanomolar (free ketone) inhibition constant. A crystal structure of the complex between the trifluoroketone and the R39 enzyme showed that a tetrahedral adduct had indeed formed with the active site serine nucleophile. The trifluoroketone moiety, therefore, should be considered along with boronic acids and phosphonates as a warhead that can be incorporated into new and effective DD-peptidase inhibitors and therefore, perhaps, antibiotics. PubMed: 23484909DOI: 10.1021/BI400048S PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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