Article

The human ACC2 CT-domain C-terminus is required for full functionality and has a novel twist

Department of Computational and Structural Chemistry, GlaxoSmithKline Inc., Five Moore Drive, Research Triangle Park, NC 27709, USA.
Acta Crystallographica Section D Biological Crystallography (Impact Factor: 7.23). 06/2009; 65(Pt 5):449-61. DOI: 10.1107/S0907444909008014
Source: PubMed

ABSTRACT Inhibition of acetyl-CoA carboxylase (ACC) may prevent lipid-induced insulin resistance and type 2 diabetes, making the enzyme an attractive pharmaceutical target. Although the enzyme is highly conserved amongst animals, only the yeast enzyme structure is available for rational drug design. The use of biophysical assays has permitted the identification of a specific C-terminal truncation of the 826-residue human ACC2 carboxyl transferase (CT) domain that is both functionally competent to bind inhibitors and crystallizes in their presence. This C-terminal truncation led to the determination of the human ACC2 CT domain-CP-640186 complex crystal structure, which revealed distinctions from the yeast-enzyme complex. The human ACC2 CT-domain C-terminus is comprised of three intertwined alpha-helices that extend outwards from the enzyme on the opposite side to the ligand-binding site. Differences in the observed inhibitor conformation between the yeast and human structures are caused by differing residues in the binding pocket.

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    • "( green ) binds at a discrete site proposed to accommodate carboxybiotin structures of CT from a number of species including E . coli and S . aureus ( Bilder et al . 2006 ) , Streptomyces coeli - color ( Diacovich et al . 2004 ) , the Mycobacterium AccD5 subunit ( Lin et al . 2006 ) as well as S . cerevisiae ( Zhang et al . 2003 ) and human ACC2 ( Madauss et al . 2009 ) have been reported . These works are summarized in Table 1 . The E . coli and S . aureus paralogues are composed of two AccA and two AccD subunits that assemble into α2β2 heterotetramers via a dimer of αβ dimers ( Bilder et al . 2006 ) . Each monomeric unit adopts two homologous structures , both belonging to the cro - tonase superfam"
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