Binding site differences revealed by crystal structures of Plasmodium falciparum and bovine acyl-CoA binding protein

• Acyl-CoA binding protein (ACBP) maintains a pool of fatty acyl-CoA molecules in the cell and plays a role in fatty acid metabolism. The biochemical properties of Plasmodium falciparum ACBP are described together with the 2.0 A resolution crystal structures of a P. falciparum ACBP-acyl-CoA complex and of bovine ACBP in two crystal forms. Overall, the bovine ACBP crystal structures are similar to the NMR structures published previously; however, the bovine and parasite ACBP structures are less similar. The parasite ACBP is shown to have a different ligand-binding pocket, leading to an acyl-CoA binding specificity different from that of bovine ACBP. Several non-conservative differences in residues that interact with the ligand were identified between the mammalian and parasite ACBPs. These, together with measured binding-specificity differences, suggest that there is a potential for the design of molecules that might selectively block the acyl-CoA binding site.

Nyckelord

acyl-CoA; structure; Plasmodium falciparum; drug design; X-ray crystallography; COENZYME-A; STRUCTURE REFINEMENT; 3-DIMENSIONAL STRUCTURE; LIGAND-BINDING; METABOLISM; EXPRESSION; SOFTWARE; RESIDUES; ACBP

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