1iel: Difference between revisions
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[[Image:1iel.gif|left|200px]] | [[Image:1iel.gif|left|200px]] | ||
'''Crystal Structure of AmpC beta-lactamase from E. coli in Complex with Ceftazidime''' | {{Structure | ||
|PDB= 1iel |SIZE=350|CAPTION= <scene name='initialview01'>1iel</scene>, resolution 2.00Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene> and <scene name='pdbligand=CAZ:ACYLATED CEFTAZIDIME'>CAZ</scene> | |||
|ACTIVITY= [http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] | |||
|GENE= | |||
}} | |||
'''Crystal Structure of AmpC beta-lactamase from E. coli in Complex with Ceftazidime''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
1IEL is a [ | 1IEL is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1IEL OCA]. | ||
==Reference== | ==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:[http:// | 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:[http://www.ncbi.nlm.nih.gov/pubmed/11478888 11478888] | ||
[[Category: Beta-lactamase]] | [[Category: Beta-lactamase]] | ||
[[Category: Escherichia coli]] | [[Category: Escherichia coli]] | ||
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[[Category: serine hydrolase]] | [[Category: serine hydrolase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 11:49:21 2008'' | ||
Revision as of 09:49, 20 March 2008
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| 1iel, resolution 2.00Å | |||||||||||||
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| Ligands: | PO4 and CAZ | ||||||||||||
| Activity: | Beta-lactamase, with EC number 3.5.2.6 | ||||||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||||||
Crystal Structure of AmpC beta-lactamase from E. coli in Complex with Ceftazidime
Overview
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.
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
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