From Proteopedia
(Difference between revisions)
proteopedia linkproteopedia link
|
|
| Line 1: |
Line 1: |
| - | [[Image:1mxo.jpg|left|200px]] | + | {{Seed}} |
| | + | [[Image:1mxo.png|left|200px]] |
| | | | |
| | <!-- | | <!-- |
| Line 9: |
Line 10: |
| | {{STRUCTURE_1mxo| PDB=1mxo | SCENE= }} | | {{STRUCTURE_1mxo| PDB=1mxo | SCENE= }} |
| | | | |
| - | '''AmpC beta-lactamase in complex with an m.carboxyphenylglycylboronic acid bearing the cephalothin R1 side chain'''
| + | ===AmpC beta-lactamase in complex with an m.carboxyphenylglycylboronic acid bearing the cephalothin R1 side chain=== |
| | | | |
| | | | |
| - | ==Overview==
| + | <!-- |
| - | 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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_12526668}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 12526668 is the PubMed ID number. |
| | + | --> |
| | + | {{ABSTRACT_PUBMED_12526668}} |
| | | | |
| | ==About this Structure== | | ==About this Structure== |
| Line 34: |
Line 38: |
| | [[Category: Cephalosporinase]] | | [[Category: Cephalosporinase]] |
| | [[Category: Serine hydrolase]] | | [[Category: Serine hydrolase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 01:50:43 2008'' | + | |
| | + | ''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
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
