Oxyimino-cephalosporins such as ceftazidime escape the hydrolytic activity of most beta-lactamases. Unfortunately, their widespread use prompted the emergence that extended-spectrum β-lactamases (ESBLs). These enzymes can confer resistances to oxyimino-cephalosporins and increase hospital mortality rates. CTX-M enzymes have become the most prevalent ESBLs, notably, Asp240Gly-harboring derivatives. CTX-M enzymes exhibit a weak hydrolytic activity against ceftazidime, because of its C7beta aminothiazol-oxyimino-amide side chain. However, the substitution Asp240Gly improves the enzymatic efficiency against this substrate. We present the comparison of crystallographic structures of CTX-M-9 and its Asp240Gly derivative in complex with an analog of ceftazidime. The structure of the two enzymes in complex with ceftazidime was modeled from these crystallographic structures and analyzed by molecular dynamics. The substitution Asp240Gly suppressed unfavorable interactions of Asp240 with the C7 side chain of ceftazidime, and induced subtle modifications in the accommodation of this side chain. Molecular modeling simulations revealed breathing motions of CTX-M, the involvement of Gly240 in orchestrated motions of active serine, the beta-3 strand and the Omega loop, which favored the key interactions of the residues 237 and 235 with ceftazidime. These results provide insights in beta-lactamase molecular dynamics, the accommodation of C7 side chain and a new mechanism for the extension of hydrolytic spectrum.
|Anno di pubblicazione:||2008|
|Titolo:||Structural and dynamic investigation of carboxypropyl oxymino group accomodation by CTX-M beta-lactamases|
|Autori:||J. DELMAS; CHEN YU; F. PRATI; F. ROBIN; SHOICHET B. K; BONNET R|
|Appare nelle tipologie:||Articolo su rivista|
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