1fsw: Difference between revisions
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|PDB= 1fsw |SIZE=350|CAPTION= <scene name='initialview01'>1fsw</scene>, resolution 1.90Å | |PDB= 1fsw |SIZE=350|CAPTION= <scene name='initialview01'>1fsw</scene>, resolution 1.90Å | ||
|SITE= | |SITE= | ||
|LIGAND= <scene name='pdbligand= | |LIGAND= <scene name='pdbligand=CTB:N-2-THIOPHEN-2-YL-ACETAMIDE+BORONIC+ACID'>CTB</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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] | |ACTIVITY= <span class='plainlinks'>[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] </span> | ||
|GENE= | |GENE= | ||
|DOMAIN= | |||
|RELATEDENTRY=[[2bls|2BLS]], [[3bls|3BLS]], [[1c3b|1C3B]], [[1fsy|1FSY]] | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1fsw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1fsw OCA], [http://www.ebi.ac.uk/pdbsum/1fsw PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1fsw RCSB]</span> | |||
}} | }} | ||
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[[Category: Shoichet, B K.]] | [[Category: Shoichet, B K.]] | ||
[[Category: Wu, C Y.]] | [[Category: Wu, C Y.]] | ||
[[Category: beta-lactamase]] | [[Category: beta-lactamase]] | ||
[[Category: cephalosporinase]] | [[Category: cephalosporinase]] | ||
[[Category: serine hydrolase]] | [[Category: serine hydrolase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 20:29:43 2008'' | ||
Revision as of 20:29, 30 March 2008
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| , resolution 1.90Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Activity: | Beta-lactamase, with EC number 3.5.2.6 | ||||||
| Related: | 2BLS, 3BLS, 1C3B, 1FSY
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
AMPC BETA-LACTAMASE FROM E. COLI COMPLEXED WITH INHIBITOR CEPHALOTHINBORONIC ACID
OverviewOverview
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 StructureAbout this Structure
1FSW is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.
ReferenceReference
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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