1mxo: Difference between revisions
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[[Image:1mxo.jpg|left|200px]] | [[Image:1mxo.jpg|left|200px]] | ||
'''AmpC beta-lactamase in complex with an m.carboxyphenylglycylboronic acid bearing the cephalothin R1 side chain''' | {{Structure | ||
|PDB= 1mxo |SIZE=350|CAPTION= <scene name='initialview01'>1mxo</scene>, resolution 1.83Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene> and <scene name='pdbligand=SM2:(1R)-1-(2-THIENYLACETYLAMINO)-1-(3-CARBOXYPHENYL)METHYLBORONIC ACID'>SM2</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= ampc ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 Escherichia coli]) | |||
}} | |||
'''AmpC beta-lactamase in complex with an m.carboxyphenylglycylboronic acid bearing the cephalothin R1 side chain''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
1MXO is a [ | 1MXO 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=1MXO OCA]. | ||
==Reference== | ==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:[http:// | 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:[http://www.ncbi.nlm.nih.gov/pubmed/12526668 12526668] | ||
[[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 12:49:34 2008'' | ||
Revision as of 10:49, 20 March 2008
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| 1mxo, resolution 1.83Å | |||||||||||||
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| Ligands: | PO4 and SM2 | ||||||||||||
| Gene: | ampc (Escherichia coli) | ||||||||||||
| Activity: | Beta-lactamase, with EC number 3.5.2.6 | ||||||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||||||
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.
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
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