View source for 2w71


==Crystal structure of Biotin carboxylase from E. coli in complex with the imidazole-pyrimidine inhibitor==
<StructureSection load='2w71' size='340' side='right'caption='[[2w71]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2w71]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W71 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2W71 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.99&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=L23:4-[1-(2,6-DICHLOROBENZYL)-2-METHYL-1H-IMIDAZOL-4-YL]PYRIMIDIN-2-AMINE'>L23</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2w71 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w71 OCA], [https://pdbe.org/2w71 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2w71 RCSB], [https://www.ebi.ac.uk/pdbsum/2w71 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2w71 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/ACCC_ECOLI ACCC_ECOLI] This protein is a component of the acetyl coenzyme A carboxylase complex; first, biotin carboxylase catalyzes the carboxylation of the carrier protein and then the transcarboxylase transfers the carboxyl group to form malonyl-CoA.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/w7/2w71_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2w71 ConSurf].
<div style="clear:both"></div>
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== Publication Abstract from PubMed ==
One explanation for the lack of novel synthetic antibacterials emerging from target-based screening is that antibacterial target space and the physicochemical properties of antibacterials are significantly different from compounds comprising eukaryotic-biased pharmaceutical screening libraries. Efforts to derive new antibacterial drugs from natural products are hampered because complex natural products do not possess desirable drug-like properties and are less tractable for medicinal chemistry. Therefore, as part of our effort to inhibit bacterial fatty acid biosynthesis through the recently validated target biotin carboxylase, we employed a unique combination of two emergent lead discovery strategies. We used both de novo fragment-based drug discovery; a rapid, resource efficient route to generate novel ligand-efficient hits and virtual screening; which employs 3D shape and electrostatic property similarity searching leveraged from existing co-crystal structures. We screened a collection of unbiased low-molecular weight molecules and identified a structurally diverse collection of weak binding but ligand-efficient molecular fragments as potential drug-like building blocks for biotin carboxylase ATP-competitive inhibitors. Through iterative cycles of structure-based drug design relying on successive fragment co-structures, we improved the potency of the initial hits by up to 3000-fold while maintaining their ligand-efficiency and desirable physicochemical properties. In one example, hit-expansion efforts resulted in a series of amino-oxazoles with antibacterial activity attributed to BC inhibition. These results successfully demonstrate that virtual screening approaches can substantially augment fragment-based screening approaches to identify novel antibacterial agents, offering an alternative strategy for antibacterial discovery particularly applicable when intimate structural knowledge of target active sites and inhibitor binding modes is available.

Discovery of Antibacterial Biotin Carboxylase Inhibitors by Virtual Screening and Fragment-Based Approaches.,Mochalkin I, Miller JR, Narasimhan LS, Thanabal V, Erdman P, Cox P, Prasad JV, Lightle S, Huband M, Stover K ACS Chem Biol. 2009 May 4. PMID:19413326<ref>PMID:19413326</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 2w71" style="background-color:#fffaf0;"></div>

==See Also==
*[[Acetyl-CoA carboxylase 3D structures|Acetyl-CoA carboxylase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli]]
[[Category: Large Structures]]
[[Category: Miller JR]]
[[Category: Mochalkin I]]