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1mxo

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{{STRUCTURE_1mxo| PDB=1mxo | SCENE= }}
{{STRUCTURE_1mxo| PDB=1mxo | SCENE= }}
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'''AmpC beta-lactamase in complex with an m.carboxyphenylglycylboronic acid bearing the cephalothin R1 side chain'''
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===AmpC beta-lactamase in complex with an m.carboxyphenylglycylboronic acid bearing the cephalothin R1 side chain===
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==Overview==
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beta-lactamases are the most widespread resistance mechanism to beta-lactam antibiotics, such as the penicillins and the cephalosporins. In an effort to combat these enzymes, a combination of stereoselective organic synthesis, enzymology, microbiology, and X-ray crystallography was used to design and evaluate new carboxyphenyl-glycylboronic acid transition-state analogue inhibitors of the class C beta-lactamase AmpC. The new compounds improve inhibition by over 2 orders of magnitude compared to analogous glycylboronic acids, with K(i) values as low as 1 nM. On the basis of the differential binding of different analogues, the introduced carboxylate alone contributes about 2.1 kcal/mol in affinity. This carboxylate corresponds to the ubiquitous C3(4)' carboxylate of beta-lactams, and this energy represents the first thermodynamic measurement of the importance of this group in molecular recognition by class C beta-lactamases. The structures of AmpC in complex with two of these inhibitors were determined by X-ray crystallography at 1.72 and 1.83 A resolution. These structures suggest a structural basis for the high affinity of the new compounds and provide templates for further design. The highest affinity inhibitor was 5 orders of magnitude more selective for AmpC than for characteristic serine proteases, such as chymotrypsin. This inhibitor reversed the resistance of clinical pathogens to the third generation cephalosporin ceftazidime; it may serve as a lead compound for drug discovery to combat bacterial resistance to beta-lactam antibiotics.
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(as it appears on PubMed at http://www.pubmed.gov), where 12526668 is the PubMed ID number.
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{{ABSTRACT_PUBMED_12526668}}
==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 Sat May 3 01:50:43 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 09:48:59 2008''

Revision as of 06:49, 28 July 2008

Image:1mxo.png

Template:STRUCTURE 1mxo

AmpC beta-lactamase in complex with an m.carboxyphenylglycylboronic acid bearing the cephalothin R1 side chain

Template:ABSTRACT PUBMED 12526668

About this Structure

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

Reference

Nanomolar inhibitors of AmpC beta-lactamase., Morandi F, Caselli E, Morandi S, Focia PJ, Blazquez J, Shoichet BK, Prati F, J Am Chem Soc. 2003 Jan 22;125(3):685-95. PMID:12526668

Page seeded by OCA on Mon Jul 28 09:48:59 2008

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