1fsy
From Proteopedia
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- | [[Image:1fsy.gif|left|200px]] | + | [[Image:1fsy.gif|left|200px]] |
- | + | ||
- | '''AMPC BETA-LACTAMASE FROM E. COLI COMPLEXED WITH INHIBITOR CLOXACILLINBORONIC ACID''' | + | {{Structure |
+ | |PDB= 1fsy |SIZE=350|CAPTION= <scene name='initialview01'>1fsy</scene>, resolution 1.75Å | ||
+ | |SITE= | ||
+ | |LIGAND= <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene> and <scene name='pdbligand=105:N-[5-METHYL-3-O-TOLYL-ISOXAZOLE-4-CARBOXYLIC ACID AMIDE] BORONIC ACID'>105</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 BETA-LACTAMASE FROM E. COLI COMPLEXED WITH INHIBITOR CLOXACILLINBORONIC ACID''' | ||
+ | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
- | 1FSY is a [ | + | 1FSY 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=1FSY OCA]. |
==Reference== | ==Reference== | ||
- | Energetic, structural, and antimicrobial analyses of beta-lactam side chain recognition by beta-lactamases., Caselli E, Powers RA, Blasczcak LC, Wu CY, Prati F, Shoichet BK, Chem Biol. 2001 Jan;8(1):17-31. PMID:[http:// | + | Energetic, structural, and antimicrobial analyses of beta-lactam side chain recognition by beta-lactamases., Caselli E, Powers RA, Blasczcak LC, Wu CY, Prati F, Shoichet BK, Chem Biol. 2001 Jan;8(1):17-31. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11182316 11182316] |
[[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 11:13:34 2008'' |
Revision as of 09:13, 20 March 2008
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, resolution 1.75Å | |||||||
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Ligands: | and | ||||||
Activity: | Beta-lactamase, with EC number 3.5.2.6 | ||||||
Coordinates: | save as pdb, mmCIF, xml |
AMPC BETA-LACTAMASE FROM E. COLI COMPLEXED WITH INHIBITOR CLOXACILLINBORONIC ACID
Overview
BACKGROUND: Penicillins and cephalosporins are among the most widely used and successful antibiotics. The emergence of resistance to these beta-lactams, most often through bacterial expression of beta-lactamases, threatens public health. To understand how beta-lactamases recognize their substrates, it would be helpful to know their binding energies. Unfortunately, these have been difficult to measure because beta-lactams form covalent adducts with beta-lactamases. This has complicated functional analyses and inhibitor design. RESULTS: To investigate the contribution to interaction energy of the key amide (R1) side chain of beta-lactam antibiotics, eight acylglycineboronic acids that bear the side chains of characteristic penicillins and cephalosporins, as well as four other analogs, were synthesized. These transition-state analogs form reversible adducts with serine beta-lactamases. Therefore, binding energies can be calculated directly from K(i) values. The K(i) values measured span four orders of magnitude against the Group I beta-lactamase AmpC and three orders of magnitude against the Group II beta-lactamase TEM-1. The acylglycineboronic acids have K(i) values as low as 20 nM against AmpC and as low as 390 nM against TEM-1. The inhibitors showed little activity against serine proteases, such as chymotrypsin. R1 side chains characteristic of beta-lactam inhibitors did not have better affinity for AmpC than did side chains characteristic of beta-lactam substrates. Two of the inhibitors reversed the resistance of pathogenic bacteria to beta-lactams in cell culture. Structures of two inhibitors in their complexes with AmpC were determined by X-ray crystallography to 1.90 A and 1.75 A resolution; these structures suggest interactions that are important to the affinity of the inhibitors. CONCLUSIONS: Acylglycineboronic acids allow us to begin to dissect interaction energies between beta-lactam side chains and beta-lactamases. Surprisingly, there is little correlation between the affinity contributed by R1 side chains and their occurrence in beta-lactam inhibitors or beta-lactam substrates of serine beta-lactamases. Nevertheless, presented in acylglycineboronic acids, these side chains can lead to inhibitors with high affinities and specificities. The structures of their complexes with AmpC give a molecular context to their affinities and may guide the design of anti-resistance compounds in this series.
About this Structure
1FSY is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.
Reference
Energetic, structural, and antimicrobial analyses of beta-lactam side chain recognition by beta-lactamases., Caselli E, Powers RA, Blasczcak LC, Wu CY, Prati F, Shoichet BK, Chem Biol. 2001 Jan;8(1):17-31. PMID:11182316
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