3V50

Complex of SHV S130G mutant beta-lactamase complexed to SA2-13

Summary for 3V50

• Entry DOI: 10.2210/pdb3v50/pdb
• Related: 2H10 2H5S 3OPP 3OPR
• Descriptor: 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)
• Functional Keywords: class a beta-lactamase fold, hydrolyze b-lactam antibiotics, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 30259.55

Authors

Wei, K.,van den Akker, F. (deposition date: 2011-12-15, release date: 2012-08-08, Last modification date: 2024-11-27)

Primary citation

Ke, W.,Rodkey, E.A.,Sampson, J.M.,Skalweit, M.J.,Sheri, A.,Pagadala, S.R.,Nottingham, M.D.,Buynak, J.D.,Bonomo, R.A.,van den Akker, F.
The importance of the trans-enamine intermediate as a beta-lactamase inhibition strategy probed in inhibitor-resistant SHV beta-lactamase variants.
Chemmedchem, 7:1002-1008, 2012

PubMed Abstract: The ability of bacteria to express inhibitor-resistant (IR) β-lactamases is stimulating the development of novel inhibitors of these enzymes. The 2'β-glutaroxypenicillinate sulfone, SA2-13, was previously designed to enhance the stabilization of the deacylation-refractory, trans-enamine inhibitory intermediate. To test whether this mode of inhibition can overcome different IR mutations, we determined the binding mode of SA2-13 through X-ray crystallography, obtaining co-crystals of the inhibitor-protein complex by soaking crystals of the IR sulfhydryl variable (SHV) β-lactamase variants S130G and M69V with the inhibitor. The 1.45 Å crystal structure of the S130G SHV:SA2-13 complex reveals that SA2-13 is still able to form the stable trans-enamine intermediate similar to the wild-type complex structure, yet with its carboxyl linker shifted deeper into the active site in the space vacated by the S130G mutation. In contrast, data from crystals of the M69V SHV:SA2-13 complex at 1.3 Å did not reveal clear inhibitor density indicating that this IR variant disfavors the trans-enamine conformation, likely due to a subtle shift in A237.

PubMed: 22438274
DOI: 10.1002/cmdc.201200006

Experimental method

X-RAY DIFFRACTION (1.45 Å)