1erq
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X-RAY CRYSTAL STRUCTURE OF TEM-1 BETA LACTAMASE IN COMPLEX WITH A DESIGNED BORONIC ACID INHIBITOR (1R)-1-ACETAMIDO-2-(3-CARBOXY-2-HYDROXYPHENYL)ETHYL BORONIC ACID
OverviewOverview
Transition state analogue boronic acid inhibitors mimicking the structures, and interactions of good penicillin substrates for the TEM-1, beta-lactamase of Escherchia coli were designed using graphic analyses, based on the enzyme's 1.7 A crystallographic structure. The synthesis of, two of these transition state analogues, (1R)-1-phenylacetamido-2-(3-carboxyphenyl)ethylboronic acid (1) and, (1R)-1-acetamido-2-(3-carboxy-2-hydroxyphenyl)ethylboronic acid (2), is, reported. Kinetic measurements show that, as designed, compounds 1 and 2, are highly effective deacylation transition state analogue inhibitors of, TEM-1 beta-lactamase, with inhibition constants of 5.9 and 13 nM, respectively. These values identify them as among the most potent, competitive inhibitors yet reported for a beta-lactamase. The best, inhibitor of the current series was, (1R)-1-phenylacetamido-2-(3-carboxyphenyl)ethylboronic acid (1, K(I) = 5.9, nM), which resembles most closely the best known substrate of TEM-1, benzylpenicillin (penicillin G). The high-resolution crystallographic, structures of these two inhibitors covalently bound to TEM-1 are also, described. In addition to verifying the design features, these two, structures show interesting and unanticipated changes in the active site, area, including strong hydrogen bond formation, water displacement, and, rearrangement of side chains. The structures provide new insights into the, further design of this potent class of beta-lactamase inhibitors.
About this StructureAbout this Structure
1ERQ is a Single protein structure of sequence from Escherichia coli with BJH as ligand. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
ReferenceReference
Structure-based design guides the improved efficacy of deacylation transition state analogue inhibitors of TEM-1 beta-Lactamase(,)., Ness S, Martin R, Kindler AM, Paetzel M, Gold M, Jensen SE, Jones JB, Strynadka NC, Biochemistry. 2000 May 9;39(18):5312-21. PMID:10820001
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