1c3b: Difference between revisions
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[[Image:1c3b.gif|left|200px]] | [[Image:1c3b.gif|left|200px]] | ||
'''AMPC BETA-LACTAMASE FROM E. COLI COMPLEXED WITH INHIBITOR, BENZO(B)THIOPHENE-2-BORONIC ACID (BZB)''' | {{Structure | ||
|PDB= 1c3b |SIZE=350|CAPTION= <scene name='initialview01'>1c3b</scene>, resolution 2.25Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=BZB:BENZO[B]THIOPHENE-2-BORONIC ACID'>BZB</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, BENZO(B)THIOPHENE-2-BORONIC ACID (BZB)''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
1C3B is a [ | 1C3B 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=1C3B OCA]. | ||
==Reference== | ==Reference== | ||
The complexed structure and antimicrobial activity of a non-beta-lactam inhibitor of AmpC beta-lactamase., Powers RA, Blazquez J, Weston GS, Morosini MI, Baquero F, Shoichet BK, Protein Sci. 1999 Nov;8(11):2330-7. PMID:[http:// | The complexed structure and antimicrobial activity of a non-beta-lactam inhibitor of AmpC beta-lactamase., Powers RA, Blazquez J, Weston GS, Morosini MI, Baquero F, Shoichet BK, Protein Sci. 1999 Nov;8(11):2330-7. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10595535 10595535] | ||
[[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 10:19:14 2008'' | ||
Revision as of 08:19, 20 March 2008
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| 1c3b, resolution 2.25Å | |||||||||||||
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| Ligands: | BZB | ||||||||||||
| 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, BENZO(B)THIOPHENE-2-BORONIC ACID (BZB)
Overview
Beta-lactamases are the major resistance mechanism to beta-lactam antibiotics and pose a growing threat to public health. Recently, bacteria have become resistant to beta-lactamase inhibitors, making this problem pressing. In an effort to overcome this resistance, non-beta-lactam inhibitors of beta-lactamases were investigated for complementarity to the structure of AmpC beta-lactamase from Escherichia coli. This led to the discovery of an inhibitor, benzo(b)thiophene-2-boronic acid (BZBTH2B), which inhibited AmpC with a Ki of 27 nM. This inhibitor is chemically dissimilar to beta-lactams, raising the question of what specific interactions are responsible for its activity. To answer this question, the X-ray crystallographic structure of BZBTH2B in complex with AmpC was determined to 2.25 A resolution. The structure reveals several unexpected interactions. The inhibitor appears to complement the conserved, R1-amide binding region of AmpC, despite lacking an amide group. Interactions between one of the boronic acid oxygen atoms, Tyr150, and an ordered water molecule suggest a mechanism for acid/base catalysis and a direction for hydrolytic attack in the enzyme catalyzed reaction. To investigate how a non-beta-lactam inhibitor would perform against resistant bacteria, BZBTH2B was tested in antimicrobial assays. BZBTH2B significantly potentiated the activity of a third-generation cephalosporin against AmpC-producing resistant bacteria. This inhibitor was unaffected by two common resistance mechanisms that often arise against beta-lactams in conjunction with beta-lactamases. Porin channel mutations did not decrease the efficacy of BZBTH2B against cells expressing AmpC. Also, this inhibitor did not induce expression of AmpC, a problem with many beta-lactams. The structure of the BZBTH2B/AmpC complex provides a starting point for the structure-based elaboration of this class of non-beta-lactam inhibitors.
About this Structure
1C3B is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.
Reference
The complexed structure and antimicrobial activity of a non-beta-lactam inhibitor of AmpC beta-lactamase., Powers RA, Blazquez J, Weston GS, Morosini MI, Baquero F, Shoichet BK, Protein Sci. 1999 Nov;8(11):2330-7. PMID:10595535
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