1o07
From Proteopedia
(New page: 200px<br /><applet load="1o07" size="450" color="white" frame="true" align="right" spinBox="true" caption="1o07, resolution 1.71Å" /> '''Crystal Structure of...) |
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| - | [[Image:1o07.gif|left|200px]]<br /><applet load="1o07" size=" | + | [[Image:1o07.gif|left|200px]]<br /><applet load="1o07" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1o07, resolution 1.71Å" /> | caption="1o07, resolution 1.71Å" /> | ||
'''Crystal Structure of the complex between Q120L/Y150E mutant of AmpC and a beta-lactam inhibitor (MXG)'''<br /> | '''Crystal Structure of the complex between Q120L/Y150E mutant of AmpC and a beta-lactam inhibitor (MXG)'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Penicillin-binding proteins (PBPs), biosynthetic enzymes of bacterial cell | + | Penicillin-binding proteins (PBPs), biosynthetic enzymes of bacterial cell wall assembly, and beta-lactamases, resistance enzymes to beta-lactam antibiotics, are related to each other from an evolutionary point of view. Massova and Mobashery (Antimicrob. Agents Chemother. 1998, 42, 1-17) have proposed that for beta-lactamases to have become effective at their function as antibiotic resistance enzymes, they would have had to undergo structure alterations such that they would not interact with the peptidoglycan, which is the substrate for PBPs. A cephalosporin analogue, 7beta-[N-Acetyl-L-alanyl-gamma-D-glutamyl-L-lysine]-3-acetoxymethyl-3-ceph em-carboxylic acid (compound 6), was conceived and synthesized to test this notion. The X-ray structure of the complex of this cephalosporin bound to the active site of the deacylation-deficient Q120L/Y150E variant of the class C AmpC beta-lactamase from Escherichia coli was solved at 1.71 A resolution. This complex revealed that the surface for interaction with the strand of peptidoglycan that acylates the active site, which is present in PBPs, is absent in the -lactamase active site. Furthermore, insertion of a peptide in the beta-lactamase active site at a location where the second strand of peptidoglycan in some PBPs binds has effectively abolished the possibility for such interaction with the beta-lactamase. A 2.6 ns dynamics simulation was carried out for the complex, which revealed that the peptidoglycan surrogate (i.e., the active-site-bound ligand) undergoes substantial motion and is not stabilized for binding within the active site. These factors taken together disclose the set of structure modifications in the antibiotic resistance enzyme that prevent it from interacting with the peptidoglycan, en route to achieving catalytic proficiency for their intended function. |
==About this Structure== | ==About this Structure== | ||
| - | 1O07 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with K and MXG 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:// | + | 1O07 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=K:'>K</scene> and <scene name='pdbligand=MXG:'>MXG</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=1O07 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Lee, W.]] | [[Category: Lee, W.]] | ||
| - | [[Category: Meroueh, S | + | [[Category: Meroueh, S O.]] |
[[Category: Minasov, G.]] | [[Category: Minasov, G.]] | ||
[[Category: Mobashery, S.]] | [[Category: Mobashery, S.]] | ||
| - | [[Category: Shoichet, B | + | [[Category: Shoichet, B K.]] |
[[Category: K]] | [[Category: K]] | ||
[[Category: MXG]] | [[Category: MXG]] | ||
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[[Category: enzyme inhibitor complex]] | [[Category: enzyme inhibitor complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:12:01 2008'' |
Revision as of 12:12, 21 February 2008
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Crystal Structure of the complex between Q120L/Y150E mutant of AmpC and a beta-lactam inhibitor (MXG)
Overview
Penicillin-binding proteins (PBPs), biosynthetic enzymes of bacterial cell wall assembly, and beta-lactamases, resistance enzymes to beta-lactam antibiotics, are related to each other from an evolutionary point of view. Massova and Mobashery (Antimicrob. Agents Chemother. 1998, 42, 1-17) have proposed that for beta-lactamases to have become effective at their function as antibiotic resistance enzymes, they would have had to undergo structure alterations such that they would not interact with the peptidoglycan, which is the substrate for PBPs. A cephalosporin analogue, 7beta-[N-Acetyl-L-alanyl-gamma-D-glutamyl-L-lysine]-3-acetoxymethyl-3-ceph em-carboxylic acid (compound 6), was conceived and synthesized to test this notion. The X-ray structure of the complex of this cephalosporin bound to the active site of the deacylation-deficient Q120L/Y150E variant of the class C AmpC beta-lactamase from Escherichia coli was solved at 1.71 A resolution. This complex revealed that the surface for interaction with the strand of peptidoglycan that acylates the active site, which is present in PBPs, is absent in the -lactamase active site. Furthermore, insertion of a peptide in the beta-lactamase active site at a location where the second strand of peptidoglycan in some PBPs binds has effectively abolished the possibility for such interaction with the beta-lactamase. A 2.6 ns dynamics simulation was carried out for the complex, which revealed that the peptidoglycan surrogate (i.e., the active-site-bound ligand) undergoes substantial motion and is not stabilized for binding within the active site. These factors taken together disclose the set of structure modifications in the antibiotic resistance enzyme that prevent it from interacting with the peptidoglycan, en route to achieving catalytic proficiency for their intended function.
About this Structure
1O07 is a Single protein structure of sequence from Escherichia coli with and as ligands. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
Reference
Structural aspects for evolution of beta-lactamases from penicillin-binding proteins., Meroueh SO, Minasov G, Lee W, Shoichet BK, Mobashery S, J Am Chem Soc. 2003 Aug 13;125(32):9612-8. PMID:12904027
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