1pwc
From Proteopedia
(New page: 200px<br /><applet load="1pwc" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pwc, resolution 1.10Å" /> '''penicilloyl acyl enz...) |
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| - | [[Image:1pwc.gif|left|200px]]<br /><applet load="1pwc" size=" | + | [[Image:1pwc.gif|left|200px]]<br /><applet load="1pwc" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1pwc, resolution 1.10Å" /> | caption="1pwc, resolution 1.10Å" /> | ||
'''penicilloyl acyl enzyme complex of the Streptomyces R61 DD-peptidase with penicillin G'''<br /> | '''penicilloyl acyl enzyme complex of the Streptomyces R61 DD-peptidase with penicillin G'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The bacterial D-alanyl-D-alanine transpeptidases (DD-peptidases) are the | + | The bacterial D-alanyl-D-alanine transpeptidases (DD-peptidases) are the killing targets of beta-lactams, the most important clinical defense against bacterial infections. However, due to the constant development of antibiotic-resistance mechanisms by bacteria, there is an ever-present need for new, more effective antimicrobial drugs. While enormous numbers of beta-lactam compounds have been tested for antibiotic activity in over 50 years of research, the success of a beta-lactam structure in terms of antibiotic activity remains unpredictable. Tipper and Strominger suggested long ago that beta-lactams inhibit DD-peptidases because they mimic the D-alanyl-D-alanine motif of the peptidoglycan substrate of these enzymes. They also predicted that beta-lactams having a peptidoglycan-mimetic side-chain might be better antibiotics than their non-specific counterparts, but decades of research have not provided any evidence for this. We have recently described two such novel beta-lactams. The first is a penicillin having the glycyl-L-alpha-amino-epsilon-pimelyl side-chain of Streptomyces strain R61 peptidoglycan, making it the "perfect penicillin" for this organism. The other is a cephalosporin with the same side-chain. Here, we describe the X-ray crystal structures of the perfect penicillin in non-covalent and covalent complexes with the Streptomyces R61 DD-peptidase. The structure of the non-covalent enzyme-inhibitor complex is the first such complex to be trapped crystallographically with a DD-peptidase. In addition, the covalent complex of the peptidyl-cephalosporin with the R61 DD-peptidase is described. Finally, two covalent complexes with the traditional beta-lactams benzylpenicillin and cephalosporin C were determined for comparison with the peptidyl beta-lactams. These structures, together with relevant kinetics data, support Tipper and Strominger's assertion that peptidoglycan-mimetic side-chains should improve beta-lactams as inhibitors of DD-peptidases. |
==About this Structure== | ==About this Structure== | ||
| - | 1PWC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Streptomyces_sp. Streptomyces sp.] with PNM as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Serine-type_D-Ala-D-Ala_carboxypeptidase Serine-type D-Ala-D-Ala carboxypeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.16.4 3.4.16.4] Full crystallographic information is available from [http:// | + | 1PWC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Streptomyces_sp. Streptomyces sp.] with <scene name='pdbligand=PNM:'>PNM</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Serine-type_D-Ala-D-Ala_carboxypeptidase Serine-type D-Ala-D-Ala carboxypeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.16.4 3.4.16.4] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PWC OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Streptomyces sp.]] | [[Category: Streptomyces sp.]] | ||
| - | [[Category: Josephine, H | + | [[Category: Josephine, H R.]] |
| - | [[Category: Kelly, J | + | [[Category: Kelly, J A.]] |
| - | [[Category: Pratt, R | + | [[Category: Pratt, R F.]] |
| - | [[Category: Silvaggi, N | + | [[Category: Silvaggi, N R.]] |
[[Category: PNM]] | [[Category: PNM]] | ||
[[Category: antibiotics]] | [[Category: antibiotics]] | ||
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[[Category: peptidoglycan]] | [[Category: peptidoglycan]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:33:14 2008'' |
Revision as of 12:33, 21 February 2008
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penicilloyl acyl enzyme complex of the Streptomyces R61 DD-peptidase with penicillin G
Overview
The bacterial D-alanyl-D-alanine transpeptidases (DD-peptidases) are the killing targets of beta-lactams, the most important clinical defense against bacterial infections. However, due to the constant development of antibiotic-resistance mechanisms by bacteria, there is an ever-present need for new, more effective antimicrobial drugs. While enormous numbers of beta-lactam compounds have been tested for antibiotic activity in over 50 years of research, the success of a beta-lactam structure in terms of antibiotic activity remains unpredictable. Tipper and Strominger suggested long ago that beta-lactams inhibit DD-peptidases because they mimic the D-alanyl-D-alanine motif of the peptidoglycan substrate of these enzymes. They also predicted that beta-lactams having a peptidoglycan-mimetic side-chain might be better antibiotics than their non-specific counterparts, but decades of research have not provided any evidence for this. We have recently described two such novel beta-lactams. The first is a penicillin having the glycyl-L-alpha-amino-epsilon-pimelyl side-chain of Streptomyces strain R61 peptidoglycan, making it the "perfect penicillin" for this organism. The other is a cephalosporin with the same side-chain. Here, we describe the X-ray crystal structures of the perfect penicillin in non-covalent and covalent complexes with the Streptomyces R61 DD-peptidase. The structure of the non-covalent enzyme-inhibitor complex is the first such complex to be trapped crystallographically with a DD-peptidase. In addition, the covalent complex of the peptidyl-cephalosporin with the R61 DD-peptidase is described. Finally, two covalent complexes with the traditional beta-lactams benzylpenicillin and cephalosporin C were determined for comparison with the peptidyl beta-lactams. These structures, together with relevant kinetics data, support Tipper and Strominger's assertion that peptidoglycan-mimetic side-chains should improve beta-lactams as inhibitors of DD-peptidases.
About this Structure
1PWC is a Single protein structure of sequence from Streptomyces sp. with as ligand. Active as Serine-type D-Ala-D-Ala carboxypeptidase, with EC number 3.4.16.4 Full crystallographic information is available from OCA.
Reference
Crystal structures of complexes between the R61 DD-peptidase and peptidoglycan-mimetic beta-lactams: a non-covalent complex with a "perfect penicillin"., Silvaggi NR, Josephine HR, Kuzin AP, Nagarajan R, Pratt RF, Kelly JA, J Mol Biol. 2005 Jan 21;345(3):521-33. PMID:15581896
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