1kr3
From Proteopedia
(New page: 200px<br /><applet load="1kr3" size="450" color="white" frame="true" align="right" spinBox="true" caption="1kr3, resolution 2.50Å" /> '''Crystal Structure of...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:1kr3.jpg|left|200px]]<br /><applet load="1kr3" size=" | + | [[Image:1kr3.jpg|left|200px]]<br /><applet load="1kr3" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1kr3, resolution 2.50Å" /> | caption="1kr3, resolution 2.50Å" /> | ||
'''Crystal Structure of the Metallo beta-Lactamase from Bacteroides fragilis (CfiA) in Complex with the Tricyclic Inhibitor SB-236050.'''<br /> | '''Crystal Structure of the Metallo beta-Lactamase from Bacteroides fragilis (CfiA) in Complex with the Tricyclic Inhibitor SB-236050.'''<br /> | ||
==Overview== | ==Overview== | ||
| - | This work describes the discovery and characterization of a novel series | + | This work describes the discovery and characterization of a novel series of tricyclic natural product-derived metallo-beta-lactamase inhibitors. Natural product screening of the Bacillus cereus II enzyme identified an extract from a strain of Chaetomium funicola with inhibitory activity against metallo-beta-lactamases. SB236050, SB238569, and SB236049 were successfully extracted and purified from this extract. The most active of these compounds was SB238569, which possessed K(i) values of 79, 17, and 3.4 microM for the Bacillus cereus II, Pseudomonas aeruginosa IMP-1, and Bacteroides fragilis CfiA metallo-beta-lactamases, respectively, yet none of the compounds exhibited any inhibitory activity against the Stenotrophomonas maltophilia L-1 metallo-beta-lactamase (50% inhibitory concentration > 1,000 microM). The lack of activity against angiotensin-converting enzyme and serine beta-lactamases demonstrated the selective nature of these compounds. The crystal structure of SB236050 complexed in the active site of CfiA has been obtained to a resolution of 2.5 A. SB236050 exhibits key polar interactions with Lys184, Asn193, and His162 and a stacking interaction with the indole ring of Trp49 in the flap, which is in the closed conformation over the active site groove. SB236050 and SB238569 also demonstrate good antibacterial synergy with meropenem. Eight micrograms of SB236050 per ml gave rise to an eightfold drop in the MIC of meropenem for two clinical isolates of B. fragilis producing CfiA, making these strains sensitive to meropenem (MIC < or = 4 microg/ml). Consequently, this series of metallo-beta-lactamase inhibitors exhibit the most promising antibacterial synergy activity so far observed against organisms producing metallo-beta-lactamases. |
==About this Structure== | ==About this Structure== | ||
| - | 1KR3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bacteroides_fragilis Bacteroides fragilis] with ZN, NA and 113 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http:// | + | 1KR3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bacteroides_fragilis Bacteroides fragilis] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=NA:'>NA</scene> and <scene name='pdbligand=113:'>113</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KR3 OCA]. |
==Reference== | ==Reference== | ||
| Line 14: | Line 14: | ||
[[Category: Beta-lactamase]] | [[Category: Beta-lactamase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Bateson, J | + | [[Category: Bateson, J H.]] |
[[Category: Boyd, H.]] | [[Category: Boyd, H.]] | ||
[[Category: Cheever, C.]] | [[Category: Cheever, C.]] | ||
| - | [[Category: Concha, N | + | [[Category: Concha, N O.]] |
[[Category: Dez, E.]] | [[Category: Dez, E.]] | ||
| - | [[Category: Fuente, J | + | [[Category: Fuente, J de la.]] |
[[Category: Gilpin, M.]] | [[Category: Gilpin, M.]] | ||
| - | [[Category: Hueso-Rodrguez, J | + | [[Category: Hueso-Rodrguez, J A.]] |
| - | [[Category: Janson, C | + | [[Category: Janson, C A.]] |
| - | [[Category: Niconovich, N | + | [[Category: Niconovich, N L.]] |
| - | [[Category: Payne, D | + | [[Category: Payne, D J.]] |
[[Category: Pearson, S.]] | [[Category: Pearson, S.]] | ||
[[Category: Prez, P.]] | [[Category: Prez, P.]] | ||
| Line 39: | Line 39: | ||
[[Category: protein-inhibitor complex]] | [[Category: protein-inhibitor complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:37:02 2008'' |
Revision as of 11:37, 21 February 2008
|
Crystal Structure of the Metallo beta-Lactamase from Bacteroides fragilis (CfiA) in Complex with the Tricyclic Inhibitor SB-236050.
Overview
This work describes the discovery and characterization of a novel series of tricyclic natural product-derived metallo-beta-lactamase inhibitors. Natural product screening of the Bacillus cereus II enzyme identified an extract from a strain of Chaetomium funicola with inhibitory activity against metallo-beta-lactamases. SB236050, SB238569, and SB236049 were successfully extracted and purified from this extract. The most active of these compounds was SB238569, which possessed K(i) values of 79, 17, and 3.4 microM for the Bacillus cereus II, Pseudomonas aeruginosa IMP-1, and Bacteroides fragilis CfiA metallo-beta-lactamases, respectively, yet none of the compounds exhibited any inhibitory activity against the Stenotrophomonas maltophilia L-1 metallo-beta-lactamase (50% inhibitory concentration > 1,000 microM). The lack of activity against angiotensin-converting enzyme and serine beta-lactamases demonstrated the selective nature of these compounds. The crystal structure of SB236050 complexed in the active site of CfiA has been obtained to a resolution of 2.5 A. SB236050 exhibits key polar interactions with Lys184, Asn193, and His162 and a stacking interaction with the indole ring of Trp49 in the flap, which is in the closed conformation over the active site groove. SB236050 and SB238569 also demonstrate good antibacterial synergy with meropenem. Eight micrograms of SB236050 per ml gave rise to an eightfold drop in the MIC of meropenem for two clinical isolates of B. fragilis producing CfiA, making these strains sensitive to meropenem (MIC < or = 4 microg/ml). Consequently, this series of metallo-beta-lactamase inhibitors exhibit the most promising antibacterial synergy activity so far observed against organisms producing metallo-beta-lactamases.
About this Structure
1KR3 is a Single protein structure of sequence from Bacteroides fragilis with , and as ligands. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
Reference
Identification of a series of tricyclic natural products as potent broad-spectrum inhibitors of metallo-beta-lactamases., Payne DJ, Hueso-Rodriguez JA, Boyd H, Concha NO, Janson CA, Gilpin M, Bateson JH, Cheever C, Niconovich NL, Pearson S, Rittenhouse S, Tew D, Diez E, Perez P, De La Fuente J, Rees M, Rivera-Sagredo A, Antimicrob Agents Chemother. 2002 Jun;46(6):1880-6. PMID:12019104
Page seeded by OCA on Thu Feb 21 13:37:02 2008
Categories: Bacteroides fragilis | Beta-lactamase | Single protein | Bateson, J H. | Boyd, H. | Cheever, C. | Concha, N O. | Dez, E. | Fuente, J de la. | Gilpin, M. | Hueso-Rodrguez, J A. | Janson, C A. | Niconovich, N L. | Payne, D J. | Pearson, S. | Prez, P. | Rees, M. | Rittenhouse, S. | Rivera-Sagredo, A. | Tew, D. | 113 | NA | ZN | Beta sandwich | Metallo | Protein-inhibitor complex
