Summary
PDB 1ERM deposited: 2000-04-06 modified: 2012-06-20
Title X-RAY CRYSTAL STRUCTURE OF TEM-1 BETA LACTAMASE IN COMPLEX WITH A DESIGNED BORONIC ACID INHIBITOR (1R)-1-ACETAMIDO-2-(3-CARBOXYPHENYL)ETHANE BORONIC ACID
Authors Gold, M., Jensen, S.E., Jones, J.B., Kindler, A.M., Martin, R., Ness, S., Paetzel, M., Strynadka, N.C.
Method X-RAY DIFFRACTION
Structure factors resolution 1.7 rfactor 0.177 rfree None
DPI
Related PDB Entries 1ERO 1ERQ
Citations

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.

Biochemistry 2000 May; 39(18):5312-5321 doi:10.1021/bi992505b

Cross References
Database source Identifier Description
PubMed 10820001 BICHAW
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
1ERM/0 1ERM 0 monomer 0 1 1 1822