3ZCZ

Crystal structure of a complex between Actinomadura R39 DD-peptidase and a trifluoroketone inhibitor

3ZCZ の概要

• エントリーDOI: 10.2210/pdb3zcz/pdb
• 分子名称: 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)
• 機能のキーワード: hydrolase, inhibitor, peptidoglycan
• 由来する生物種: ACTINOMADURA SP. R39
• 細胞内の位置: Secreted: P39045
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 193843.67

構造登録者

Sauvage, E.,Herman, R.,Kerff, F.,Rocaboy, M.,Charlier, P. (登録日: 2012-11-23, 公開日: 2013-03-27, 最終更新日: 2024-11-13)

主引用文献

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

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: 23484909
DOI: 10.1021/BI400048S

実験手法

X-RAY DIFFRACTION (2.6 Å)