2hdu
From Proteopedia
(New page: 200px<br /><applet load="2hdu" size="450" color="white" frame="true" align="right" spinBox="true" caption="2hdu, resolution 1.490Å" /> '''AmpC beta-lactamase...) |
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| - | [[Image:2hdu.gif|left|200px]]<br /><applet load="2hdu" size=" | + | [[Image:2hdu.gif|left|200px]]<br /><applet load="2hdu" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2hdu, resolution 1.490Å" /> | caption="2hdu, resolution 1.490Å" /> | ||
'''AmpC beta-lactamase in complex with 2-acetamidothiophene-3-carboxylic acid'''<br /> | '''AmpC beta-lactamase in complex with 2-acetamidothiophene-3-carboxylic acid'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Fragment-based screens test multiple low-molecular weight molecules for | + | Fragment-based screens test multiple low-molecular weight molecules for binding to a target. Fragments often bind with low affinities but typically have better ligand efficiencies (DeltaG(bind)/heavy atom count) than traditional screening hits. This efficiency, combined with accompanying atomic-resolution structures, has made fragments popular starting points for drug discovery programs. Fragment-based design adopts a constructive strategy: affinity is enhanced either by cycles of functional-group addition or by joining two independent fragments together. The final inhibitor is expected to adopt the same geometry as the original fragment hit. Here we consider whether the inverse, deconstructive logic also applies--can one always parse a higher-affinity inhibitor into fragments that recapitulate the binding geometry of the larger molecule? Cocrystal structures of fragments deconstructed from a known beta-lactamase inhibitor suggest that this is not always the case. |
==About this Structure== | ==About this Structure== | ||
| - | 2HDU 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, PO4 and F12 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:// | + | 2HDU 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>, <scene name='pdbligand=PO4:'>PO4</scene> and <scene name='pdbligand=F12:'>F12</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=2HDU OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Babaoglu, K.]] | [[Category: Babaoglu, K.]] | ||
| - | [[Category: Shoichet, B | + | [[Category: Shoichet, B K.]] |
[[Category: F12]] | [[Category: F12]] | ||
[[Category: K]] | [[Category: K]] | ||
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[[Category: ampc beta-lactamase fragment-based drug design]] | [[Category: ampc beta-lactamase fragment-based drug design]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:40:47 2008'' |
Revision as of 15:40, 21 February 2008
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AmpC beta-lactamase in complex with 2-acetamidothiophene-3-carboxylic acid
Overview
Fragment-based screens test multiple low-molecular weight molecules for binding to a target. Fragments often bind with low affinities but typically have better ligand efficiencies (DeltaG(bind)/heavy atom count) than traditional screening hits. This efficiency, combined with accompanying atomic-resolution structures, has made fragments popular starting points for drug discovery programs. Fragment-based design adopts a constructive strategy: affinity is enhanced either by cycles of functional-group addition or by joining two independent fragments together. The final inhibitor is expected to adopt the same geometry as the original fragment hit. Here we consider whether the inverse, deconstructive logic also applies--can one always parse a higher-affinity inhibitor into fragments that recapitulate the binding geometry of the larger molecule? Cocrystal structures of fragments deconstructed from a known beta-lactamase inhibitor suggest that this is not always the case.
About this Structure
2HDU 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
Deconstructing fragment-based inhibitor discovery., Babaoglu K, Shoichet BK, Nat Chem Biol. 2006 Dec;2(12):720-3. Epub 2006 Oct 29. PMID:17072304
Page seeded by OCA on Thu Feb 21 17:40:47 2008
