4JPM

Structure of SHV-1 beta-lactamase in complex with the 7-alkylidenecephalosporin DCM-1-10 at 1.14 Ang resolution

Summary for 4JPM

• Entry DOI: 10.2210/pdb4jpm/pdb
• Related: 4FH4
• Descriptor: Beta-lactamase SHV-1, CYCLOHEXYL-HEXYL-BETA-D-MALTOSIDE, 7-alkylidenecephalosporin DCM-1-10, bound form, ... (5 entities in total)
• Functional Keywords: class a beta-lactamase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 32918.90

Authors

Rodkey, E.A.,van den Akker, F. (deposition date: 2013-03-19, release date: 2013-12-04, Last modification date: 2024-11-20)

Primary citation

Rodkey, E.A.,McLeod, D.C.,Bethel, C.R.,Smith, K.M.,Xu, Y.,Chai, W.,Che, T.,Carey, P.R.,Bonomo, R.A.,van den Akker, F.,Buynak, J.D.
beta-Lactamase Inhibition by 7-Alkylidenecephalosporin Sulfones: Allylic Transposition and Formation of an Unprecedented Stabilized Acyl-Enzyme.
J.Am.Chem.Soc., 135:18358-18369, 2013

PubMed Abstract: The inhibition of the class A SHV-1 β-lactamase by 7-(tert-butoxycarbonyl)methylidenecephalosporin sulfone was examined kinetically, spectroscopically, and crystallographically. An 1.14 Å X-ray crystal structure shows that the stable acyl-enzyme, which incorporates an eight-membered ring, is a covalent derivative of Ser70 linked to the 7-carboxy group of 2-H-5,8-dihydro-1,1-dioxo-1,5-thiazocine-4,7-dicarboxylic acid. A cephalosporin-derived enzyme complex of this type is unprecedented, and the rearrangement leading to its formation may offer new possibilities for inhibitor design. The observed acyl-enzyme derives its stability from the resonance stabilization conveyed by the β-aminoacrylate (i.e., vinylogous urethane) functionality as there is relatively little interaction of the eight-membered ring with active site residues. Two mechanistic schemes are proposed, differing in whether, subsequent to acylation of the active site serine and opening of the β-lactam, the resultant dihydrothiazine fragments on its own or is assisted by an adjacent nucleophilic atom, in the form of the carbonyl oxygen of the C7 tert-butyloxycarbonyl group. This compound was also found to be a submicromolar inhibitor of the class C ADC-7 and PDC-3 β-lactamases.

PubMed: 24219313
DOI: 10.1021/ja403598g

Experimental method

X-RAY DIFFRACTION (1.14 Å)