4FCF

K234R: apo structure of inhibitor resistant beta-lactamase

Summary for 4FCF

• Entry DOI: 10.2210/pdb4fcf/pdb
• Descriptor: Beta-lactamase SHV-1, CYCLOHEXYL-HEXYL-BETA-D-MALTOSIDE, 2-AMINOETHANESULFONIC ACID, ... (4 entities in total)
• Functional Keywords: class a beta-lactamse, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 30077.38

Authors

Rodkey, E.A.,van den Akker, F. (deposition date: 2012-05-24, release date: 2012-12-26, Last modification date: 2013-10-02)

Primary citation

Winkler, M.L.,Rodkey, E.A.,Taracila, M.A.,Drawz, S.M.,Bethel, C.R.,Papp-Wallace, K.M.,Smith, K.M.,Xu, Y.,Dwulit-Smith, J.R.,Romagnoli, C.,Caselli, E.,Prati, F.,van den Akker, F.,Bonomo, R.A.
Design and exploration of novel boronic acid inhibitors reveals important interactions with a clavulanic acid-resistant sulfhydryl-variable (SHV) beta-lactamase.
J.Med.Chem., 56:1084-1097, 2013

PubMed Abstract: Inhibitor resistant (IR) class A β-lactamases pose a significant threat to many current antibiotic combinations. The K234R substitution in the SHV β-lactamase, from Klebsiella pneumoniae , results in resistance to ampicillin/clavulanate. After site-saturation mutagenesis of Lys-234 in SHV, microbiological and biochemical characterization of the resulting β-lactamases revealed that only -Arg conferred resistance to ampicillin/clavulanate. X-ray crystallography revealed two conformations of Arg-234 and Ser-130 in SHV K234R. The movement of Ser-130 is the principal cause of the observed clavulanate resistance. A panel of boronic acid inhibitors was designed and tested against SHV-1 and SHV K234R. A chiral ampicillin analogue was discovered to have a 2.4 ± 0.2 nM K(i) for SHV K234R; the chiral ampicillin analogue formed a more complex hydrogen-bonding network in SHV K234R vs SHV-1. Consideration of the spatial position of Ser-130 and Lys-234 and this hydrogen-bonding network will be important in the design of novel antibiotics targeting IR β-lactamases.

PubMed: 23252553
DOI: 10.1021/jm301490d

Experimental method

X-RAY DIFFRACTION (1.09 Å)