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| | {{STRUCTURE_1iel| PDB=1iel | SCENE= }} | | {{STRUCTURE_1iel| PDB=1iel | SCENE= }} |
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| - | '''Crystal Structure of AmpC beta-lactamase from E. coli in Complex with Ceftazidime'''
| + | ===Crystal Structure of AmpC beta-lactamase from E. coli in Complex with Ceftazidime=== |
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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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_11478888}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 11478888 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_11478888}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Cephalosporinase]] | | [[Category: Cephalosporinase]] |
| | [[Category: Serine hydrolase]] | | [[Category: Serine hydrolase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 19:54:58 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 10:51:05 2008'' |
Revision as of 07:51, 1 July 2008
Template:STRUCTURE 1iel
Crystal Structure of AmpC beta-lactamase from E. coli in Complex with Ceftazidime
Template:ABSTRACT PUBMED 11478888
About this Structure
1IEL 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
Page seeded by OCA on Tue Jul 1 10:51:05 2008
