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1iem

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{{STRUCTURE_1iem| PDB=1iem | SCENE= }}
{{STRUCTURE_1iem| PDB=1iem | SCENE= }}
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'''Crystal Structure of AmpC beta-lactamase from E. coli in Complex with a Boronic Acid Inhibitor (1, CefB4)'''
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===Crystal Structure of AmpC beta-lactamase from E. coli in Complex with a Boronic Acid Inhibitor (1, CefB4)===
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==Overview==
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Third-generation cephalosporins are widely used beta-lactam antibiotics that resist hydrolysis by beta-lactamases. Recently, mutant beta-lactamases that rapidly inactivate these drugs have emerged. To investigate why third-generation cephalosporins are relatively stable to wild-type class C beta-lactamases and how mutant enzymes might overcome this, the structures of the class C beta-lactamase AmpC in complex with the third-generation cephalosporin ceftazidime and with a transition-state analogue of ceftazidime were determined by X-ray crystallography to 2.0 and 2.3 A resolution, respectively. Comparison of the acyl-enzyme structures of ceftazidime and loracarbef, a beta-lactam substrate, reveals that the conformation of ceftazidime in the active site differs from that of substrates. Comparison of the structures of the acyl-enzyme intermediate and the transition-state analogue suggests that ceftazidime blocks formation of the tetrahedral transition state, explaining why it is an inhibitor of AmpC. Ceftazidime cannot adopt a conformation competent for catalysis due to steric clashes that would occur with conserved residues Val211 and Tyr221. The X-ray crystal structure of the mutant beta-lactamase GC1, which has improved activity against third-generation cephalosporins, suggests that a tandem tripeptide insertion in the Omega loop, which contains Val211, has caused a shift of this residue and also of Tyr221 that would allow ceftazidime and other third-generation cephalosporins to adopt a more catalytically competent conformation. These structural differences may explain the extended spectrum activity of GC1 against this class of cephalosporins. In addition, the complexed structure of the transition-state analogue inhibitor (K(i) 20 nM) with AmpC reveals potential opportunities for further inhibitor design.
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{{ABSTRACT_PUBMED_11478888}}
==About this Structure==
==About this Structure==
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[[Category: Cephalosporinase]]
[[Category: Cephalosporinase]]
[[Category: Serine hydrolase]]
[[Category: Serine hydrolase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 10:51:13 2008''

Revision as of 07:51, 1 July 2008

Image:1iem.png

Template:STRUCTURE 1iem

Crystal Structure of AmpC beta-lactamase from E. coli in Complex with a Boronic Acid Inhibitor (1, CefB4)

Template:ABSTRACT PUBMED 11478888

About this Structure

1IEM is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.

Reference

Structures of ceftazidime and its transition-state analogue in complex with AmpC beta-lactamase: implications for resistance mutations and inhibitor design., Powers RA, Caselli E, Focia PJ, Prati F, Shoichet BK, Biochemistry. 2001 Aug 7;40(31):9207-14. PMID:11478888

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