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| - | [[Image:1c3b.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_1c3b| PDB=1c3b | SCENE= }} | | {{STRUCTURE_1c3b| PDB=1c3b | SCENE= }} |
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| - | '''AMPC BETA-LACTAMASE FROM E. COLI COMPLEXED WITH INHIBITOR, BENZO(B)THIOPHENE-2-BORONIC ACID (BZB)'''
| + | ===AMPC BETA-LACTAMASE FROM E. COLI COMPLEXED WITH INHIBITOR, BENZO(B)THIOPHENE-2-BORONIC ACID (BZB)=== |
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| - | ==Overview==
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| - | 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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_10595535}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 10595535 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_10595535}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Cephalosporinase]] | | [[Category: Cephalosporinase]] |
| | [[Category: Serine hydrolase]] | | [[Category: Serine hydrolase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 12:16:32 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 20:08:54 2008'' |
Revision as of 17:08, 30 June 2008
Template:STRUCTURE 1c3b
AMPC BETA-LACTAMASE FROM E. COLI COMPLEXED WITH INHIBITOR, BENZO(B)THIOPHENE-2-BORONIC ACID (BZB)
Template:ABSTRACT PUBMED 10595535
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
Page seeded by OCA on Mon Jun 30 20:08:54 2008
