2H5S

SA2-13 penam sulfone complexed to wt SHV-1 beta-lactamase

2H5S の概要

• エントリーDOI: 10.2210/pdb2h5s/pdb
• 関連するPDBエントリー: 1RCJ
• 分子名称: SHV-1 beta-lactamase, (3R)-4-[(4-CARBOXYBUTANOYL)OXY]-N-[(1E)-3-OXOPROP-1-EN-1-YL]-3-SULFINO-D-VALINE, CYCLOHEXYL-HEXYL-BETA-D-MALTOSIDE, ... (4 entities in total)
• 機能のキーワード: beta-lactamase inhibitor, drug design, hydrolase
• 由来する生物種: Klebsiella pneumoniae
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30289.57

構造登録者

van den Akker, F.,Padayatti, P.S. (登録日: 2006-05-27, 公開日: 2006-10-17, 最終更新日: 2024-11-13)

主引用文献

Padayatti, P.S.,Sheri, A.,Totir, M.A.,Helfand, M.S.,Carey, M.P.,Anderson, V.E.,Carey, P.R.,Bethel, C.R.,Bonomo, R.A.,Buynak, J.D.,van den Akker, F.
Rational Design of a beta-Lactamase Inhibitor Achieved via Stabilization of the trans-Enamine Intermediate: 1.28 A Crystal Structure of wt SHV-1 Complex with a Penam Sulfone.
J.Am.Chem.Soc., 128:13235-13242, 2006

PubMed Abstract: beta-Lactamases are one of the major causes of antibiotic resistance in Gram negative bacteria. The continuing evolution of beta-lactamases that are capable of hydrolyzing our most potent beta-lactams presents a vexing clinical problem, in particular since a number of them are resistant to inhibitors. The efficient inhibition of these enzymes is therefore of great clinical importance. Building upon our previous structural studies that examined tazobactam trapped as a trans-enamine intermediate in a deacylation deficient SHV variant, we designed a novel penam sulfone derivative that forms a more stable trans-enamine intermediate. We report here the 1.28 A resolution crystal structure of wt SHV-1 in complex with a rationally designed penam sulfone, SA2-13. The compound is covalently bound to the active site of wt SHV-1 similar to tazobactam yet forms an additional salt-bridge with K234 and hydrogen bonds with S130 and T235 to stabilize the trans-enamine intermediate. Kinetic measurements show that SA2-13, once reacted with SHV-1 beta-lactamase, is about 10-fold slower at being released from the enzyme compared to tazobactam. Stabilizing the trans-enamine intermediate represents a novel strategy for the rational design of mechanism-based class A beta-lactamase inhibitors.

PubMed: 17017804
DOI: 10.1021/ja063715w

実験手法

X-RAY DIFFRACTION (1.28 Å)