2V58

CRYSTAL STRUCTURE OF BIOTIN CARBOXYLASE FROM E.COLI IN COMPLEX WITH POTENT INHIBITOR 1

Summary for 2V58

• Entry DOI: 10.2210/pdb2v58/pdb
• Related: 1BNC 1DV1 1DV2 1K69 2GPS 2GPW 2J9G 2V59 2V5A 2VR1
• Descriptor: BIOTIN CARBOXYLASE, 6-(2,6-dibromophenyl)pyrido[2,3-d]pyrimidine-2,7-diamine, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: fatty acid biosynthesis, biotin carboxylase, nucleotide-binding, atp-binding, antibacterial, lipid synthesis, fas, ligase, biotin, bacterial, inhibitor
• Biological source: ESCHERICHIA COLI
• Total number of polymer chains: 2
• Total formula weight: 99634.32

Authors

Mochalkin, I.,Miller, J.R. (deposition date: 2008-10-02, release date: 2009-01-13, Last modification date: 2023-12-13)

Primary citation

Miller, J.R.,Dunham, S.,Mochalkin, I.,Banotai, C.,Bowman, M.,Buist, S.,Dunkle, B.,Hanna, D.,Harwood, H.J.,Huband, M.D.,Karnovsky, A.,Kuhn, M.,Limberakis, C.,Liu, J.Y.,Mehrens, S.,Mueller, W.T.,Narasimhan, L.,Ogden, A.,Ohren, J.,Prasad, J.V.,Shelly, J.A.,Skerlos, L.,Sulavik, M.,Thomas, V.H.,Vanderroest, S.,Wang, L.,Wang, Z.,Whitton, A.,Zhu, T.,Stover, C.K.
A Class of Selective Antibacterials Derived from a Protein Kinase Inhibitor Pharmacophore.
Proc.Natl.Acad.Sci.USA, 106:1737-, 2009

PubMed Abstract: 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.

PubMed: 19164768
DOI: 10.1073/PNAS.0811275106

Experimental method

X-RAY DIFFRACTION (2.1 Å)