1pzo
From Proteopedia
(New page: 200px<br /><applet load="1pzo" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pzo, resolution 1.90Å" /> '''TEM-1 Beta-Lactamase...) |
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| - | [[Image:1pzo.gif|left|200px]]<br /><applet load="1pzo" size=" | + | [[Image:1pzo.gif|left|200px]]<br /><applet load="1pzo" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1pzo, resolution 1.90Å" /> | caption="1pzo, resolution 1.90Å" /> | ||
'''TEM-1 Beta-Lactamase in Complex with a Novel, Core-Disrupting, Allosteric Inhibitor'''<br /> | '''TEM-1 Beta-Lactamase in Complex with a Novel, Core-Disrupting, Allosteric Inhibitor'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Although inhibitors typically bind pre-formed sites on proteins, it is | + | Although inhibitors typically bind pre-formed sites on proteins, it is theoretically possible to inhibit by disrupting the folded structure of a protein or, in the limit, to bind preferentially to the unfolded state. Equilibria defining how such molecules act are well understood, but structural models for such binding are unknown. Two novel inhibitors of beta-lactamase were found to destabilize the enzyme at high temperatures, but at lower temperatures showed no preference for destabilized mutant enzymes versus stabilized mutants. X-ray crystal structures showed that both inhibitors bound to a cryptic site in beta-lactamase, which the inhibitors themselves created by forcing apart helixes 11 and 12. This opened up a portion of the hydrophobic core of the protein, into which these two inhibitors bind. Although this binding site is 16 A from the center of the active site, the conformational changes were transmitted through a sequence of linked motions to a key catalytic residue, Arg244, which in the complex adopts conformations very different from those in catalytically competent enzyme conformations. These structures offer a detailed view of what has heretofore been a theoretical construct, and suggest the possibility for further design against this novel site. |
==About this Structure== | ==About this Structure== | ||
| - | 1PZO 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 CBT as [http://en.wikipedia.org/wiki/ligand ligand]. 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:// | + | 1PZO 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=CBT:'>CBT</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. 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=1PZO OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Escherichia coli]] | [[Category: Escherichia coli]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Horn, J | + | [[Category: Horn, J R.]] |
| - | [[Category: Shoichet, B | + | [[Category: Shoichet, B K.]] |
[[Category: CBT]] | [[Category: CBT]] | ||
[[Category: beta-lactamase]] | [[Category: beta-lactamase]] | ||
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[[Category: novel allosteric inhibitor]] | [[Category: novel allosteric inhibitor]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:34:16 2008'' |
Revision as of 12:34, 21 February 2008
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TEM-1 Beta-Lactamase in Complex with a Novel, Core-Disrupting, Allosteric Inhibitor
Overview
Although inhibitors typically bind pre-formed sites on proteins, it is theoretically possible to inhibit by disrupting the folded structure of a protein or, in the limit, to bind preferentially to the unfolded state. Equilibria defining how such molecules act are well understood, but structural models for such binding are unknown. Two novel inhibitors of beta-lactamase were found to destabilize the enzyme at high temperatures, but at lower temperatures showed no preference for destabilized mutant enzymes versus stabilized mutants. X-ray crystal structures showed that both inhibitors bound to a cryptic site in beta-lactamase, which the inhibitors themselves created by forcing apart helixes 11 and 12. This opened up a portion of the hydrophobic core of the protein, into which these two inhibitors bind. Although this binding site is 16 A from the center of the active site, the conformational changes were transmitted through a sequence of linked motions to a key catalytic residue, Arg244, which in the complex adopts conformations very different from those in catalytically competent enzyme conformations. These structures offer a detailed view of what has heretofore been a theoretical construct, and suggest the possibility for further design against this novel site.
About this Structure
1PZO is a Single protein structure of sequence from Escherichia coli with as ligand. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
Reference
Allosteric inhibition through core disruption., Horn JR, Shoichet BK, J Mol Biol. 2004 Mar 5;336(5):1283-91. PMID:15037085
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