1a7t
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METALLO-BETA-LACTAMASE WITH MES
OverviewOverview
As part of a structure-aided effort to design clinically useful inhibitors, of metallo-beta-lactamases, the X-ray crystal structure of a complex, between the metallo-beta-lactamase from Bacteroides fragilis and, 4-morpholinoethanesulfonic acid (MES) has been determined and a model for, the structure has been refined to a crystallographic R-factor of 0.151 for, data between 10.0- and 1.85-A resolution. Although the binding of MES was, an adventitious result of the use of MES as a buffer in the, crystallization mixture, MES was subsequently shown to be a competitive, inhibitor of the enzyme, with a Ki of 23 +/- 5 mM. MES binds in the same, fashion to both of the molecules in the crystallographic asymmetric unit;, both direct and solvent-mediated hydrogen bonds to the protein and to the, binuclear zinc cluster are observed, involving the oxygens of the sulfonic, acid group and the nitrogen of the morpholino ring. In addition, there are, hydrophobic interactions between the morpholino ring and residues in the, flexible beta-strand of the enzyme between residues 26 and 36. Comparison, of this structure with the previously reported unliganded structures of, the same enzyme [Concha, N. O., Rasmussen, B. A., Bush, K., and Herzberg, O. (1996) Structure 4, 823-836; Carfi, A., Duee, E., Paul-Soto, R., Galleni, M., Frere, J. -M., and Dideberg, O. (1998) Acta Crystallogr. D54, 47-57] reveals that although the overall conservation of structure in the, three different crystal lattices is very high, binding of MES is, correlated with a significant change in the conformation of this, beta-strand. The flexibility of this beta-strand will be an important, consideration in the design of inhibitors of the metallo-beta-lactamases.
About this StructureAbout this Structure
1A7T is a Single protein structure of sequence from Bacteroides fragilis with ZN, NA and MES as ligands. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
ReferenceReference
Unanticipated inhibition of the metallo-beta-lactamase from Bacteroides fragilis by 4-morpholineethanesulfonic acid (MES): a crystallographic study at 1.85-A resolution., Fitzgerald PM, Wu JK, Toney JH, Biochemistry. 1998 May 12;37(19):6791-800. PMID:9578564
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