1jwv
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(New page: 200px<br /><applet load="1jwv" size="450" color="white" frame="true" align="right" spinBox="true" caption="1jwv, resolution 1.85Å" /> '''Crystal structure of...)
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Revision as of 16:31, 20 November 2007
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Crystal structure of G238A mutant of TEM-1 beta-lactamase in complex with a boronic acid inhibitor (sefb4)
Overview
Pressured by antibiotic use, resistance enzymes have been evolving new, activities. Does such evolution have a cost? To investigate this question, at the molecular level, clinically isolated mutants of the beta-lactamase, TEM-1 were studied. When purified, mutant enzymes had increased activity, against cephalosporin antibiotics but lost both thermodynamic stability, and kinetic activity against their ancestral targets, penicillins. The, X-ray crystallographic structures of three mutant enzymes were determined., These structures suggest that activity gain and stability loss is related, to an enlarged active site cavity in the mutant enzymes. In several, clinically isolated mutant enzymes, a secondary substitution is observed, far from the active site (Met182-->Thr). This substitution had little, effect on enzyme activity but restored stability lost by substitutions, near the active site. This regained stability conferred an advantage in, vivo. This pattern of stability loss and restoration may be common in the, evolution of new enzyme activity.
About this Structure
1JWV is a Single protein structure of sequence from Escherichia coli with K and CB4 as ligands. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
Reference
Evolution of an antibiotic resistance enzyme constrained by stability and activity trade-offs., Wang X, Minasov G, Shoichet BK, J Mol Biol. 2002 Jun 28;320(1):85-95. PMID:12079336
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