1ymx
X-ray crystallographic structure of CTX-M-9 beta-lactamase covalently linked to cefoxitin
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OverviewOverview
CTX-M enzymes are an emerging group of extended spectrum beta-lactamases, (ESBLs) that hydrolyze not only the penicillins but also the first-, second-, and third-generation cephalosporins. Although they have become, the most frequently observed ESBLs in certain areas, there are few, effective inhibitors and relatively little is known about their detailed, mechanism. Here we describe the X-ray crystal structures of CTX-M enzymes, in complex with different transition-state analogues and beta-lactam, inhibitors, representing the enzyme as it progresses from its acylation, transition state to its acyl enzyme complex to the deacylation transition, state. As the enzyme moves along this reaction coordinate, two key, catalytic residues, Lys73 and Glu166, change conformations, tracking the, state of the reaction. Unexpectedly, the acyl enzyme complex with the, beta-lactam inhibitor cefoxitin still has the catalytic water bound; this, water had been predicted to be displaced by the unusual 7alpha-methoxy of, the inhibitor. Instead, the 7alpha-group appears to inhibit by preventing, the formation of the deacylation transition state through steric, hindrance. From an inhibitor design standpoint, we note that the best of, the reversible inhibitors, a ceftazidime-like boronic acid compound, binds, to CTX-M-16 with a K(i) value of 4 nM. When used together in cell culture, this inhibitor reversed cefotaxime resistance in CTX-M-producing bacteria., The structure of its complex with CTX-M enzyme and the structural view of, the reaction coordinate described here provide templates for inhibitor, design and intervention to combat this family of antibiotic resistance, enzymes.
About this StructureAbout this Structure
1YMX is a Single protein structure of sequence from Escherichia coli with CFX as ligand. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
ReferenceReference
Structure, function, and inhibition along the reaction coordinate of CTX-M beta-lactamases., Chen Y, Shoichet B, Bonnet R, J Am Chem Soc. 2005 Apr 20;127(15):5423-34. PMID:15826180
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