2hdr
From Proteopedia
(New page: 200px<br /><applet load="2hdr" size="450" color="white" frame="true" align="right" spinBox="true" caption="2hdr, resolution 2.200Å" /> '''AmpC beta-lactamase...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:2hdr.gif|left|200px]]<br /><applet load="2hdr" size=" | + | [[Image:2hdr.gif|left|200px]]<br /><applet load="2hdr" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2hdr, resolution 2.200Å" /> | caption="2hdr, resolution 2.200Å" /> | ||
'''AmpC beta-lactamase in complex with 4-Amino-3-hydroxybenzoic acid'''<br /> | '''AmpC beta-lactamase in complex with 4-Amino-3-hydroxybenzoic 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== | ||
| - | 2HDR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli_k12 Escherichia coli k12] with PO4 and 4A3 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:// | + | 2HDR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli_k12 Escherichia coli k12] with <scene name='pdbligand=PO4:'>PO4</scene> and <scene name='pdbligand=4A3:'>4A3</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=2HDR OCA]. |
==Reference== | ==Reference== | ||
| Line 15: | Line 15: | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Babaoglu, K.]] | [[Category: Babaoglu, K.]] | ||
| - | [[Category: Shoichet, B | + | [[Category: Shoichet, B K.]] |
[[Category: 4A3]] | [[Category: 4A3]] | ||
[[Category: PO4]] | [[Category: PO4]] | ||
[[Category: ampc fragment-based drug design beta-lactamase]] | [[Category: ampc fragment-based drug design beta-lactamase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:40:49 2008'' |
Revision as of 15:40, 21 February 2008
|
AmpC beta-lactamase in complex with 4-Amino-3-hydroxybenzoic 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
2HDR is a Single protein structure of sequence from Escherichia coli k12 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 17:40:49 2008
