View source for 2v59


==CRYSTAL STRUCTURE OF BIOTIN CARBOXYLASE FROM E.COLI IN COMPLEX WITH POTENT INHIBITOR 2==
<StructureSection load='2v59' size='340' side='right'caption='[[2v59]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2v59]] 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=2V59 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2V59 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]] 2.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LZK:6-(2,6-DIMETHOXYPHENYL)PYRIDO[2,3-D]PYRIMIDINE-2,7-DIAMINE'>LZK</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=2v59 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2v59 OCA], [https://pdbe.org/2v59 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2v59 RCSB], [https://www.ebi.ac.uk/pdbsum/2v59 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2v59 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.
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== Publication Abstract from PubMed ==
As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious Gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity.

A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore.,Miller JR, Dunham S, Mochalkin I, Banotai C, Bowman M, Buist S, Dunkle B, Hanna D, Harwood HJ, Huband MD, Karnovsky A, Kuhn M, Limberakis C, Liu JY, Mehrens S, Mueller WT, Narasimhan L, Ogden A, Ohren J, Prasad JV, Shelly JA, Skerlos L, Sulavik M, Thomas VH, Vanderroest S, Wang L, Wang Z, Whitton A, Zhu T, Stover CK Proc Natl Acad Sci U S A. 2009 Jan 22. PMID:19164768<ref>PMID:19164768</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2v59" 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]]