1tdg
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Complex of S130G SHV-1 beta-lactamase with tazobactam
OverviewOverview
A bacterial response to the clinical use of class A beta-lactamase, inhibitors such as tazobactam and clavulanic acid is the expression of, variant beta-lactamases with weaker binding affinities for these, mechanism-based inhibitors. Some of these inhibitor-resistant variants, contain a glycine mutation at Ser130, a conserved active site residue, known to be adventitiously involved in the inhibition mechanism. The, crystallographic structure of a complex of tazobactam with the Ser130Gly, variant of the class A SHV-1 beta-lactamase has been determined to 1.8 A, resolution. Two reaction intermediates are observed. The primary, intermediate is an acyclic species bound to the reactive Ser70. It is, poorly primed for catalytic hydrolysis because its ester carbonyl group is, completely displaced from the enzyme's oxyanion hole. A smaller fraction, of the enzyme contains a Ser70-bound aldehyde resulting from hydrolytic, loss of the triazoyl-sulfinyl amino acid moiety from the primary species., This first structure of a class A beta-lactamase lacking Ser130, the side, chain of which functions in beta-lactam binding and possibly in catalysis, gives crystallographic evidence that the acylation step of beta-lactam, turnover can occur without Ser130. Unexpectedly, the crystal structure of, the uncomplexed Ser130Gly enzyme, also determined to 1.8 A resolution, shows that a critical Glu166-activated water molecule is missing from the, catalytic site. Comparison of this uncomplexed variant with the wild-type, structure reveals that Ser130 is required for orienting the side chain of, Ser70 and ensuring the hydrogen bonding of Ser70 to both Lys73 and the, catalytic water molecule.
About this StructureAbout this Structure
1TDG is a Single protein structure of sequence from Klebsiella pneumoniae with MA4, TBE, MDD, MRD and MPD as ligands. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
ReferenceReference
Inhibitor-resistant class A beta-lactamases: consequences of the Ser130-to-Gly mutation seen in Apo and tazobactam structures of the SHV-1 variant., Sun T, Bethel CR, Bonomo RA, Knox JR, Biochemistry. 2004 Nov 9;43(44):14111-7. PMID:15518561
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