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![[Figure 11]](gm5114fig11mag.jpg)
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Figure 11
Nonstandard binding modes of acidic ligands in hFABP4. (a) The acidic moiety is at the center of the ligand in 7fwp. The ligand adopts a U shape and the hydrophobic interactions are similar to the palmitate in 2hnx (black), but the overall orientations of the ligands are different. (b) Binding mode of triazolo-pyrimidinone inhibitors. The isoforms hFABP3, hFABP4 and hFABP5 are colored gray, green and blue, respectively. The canonical orientations of the hFABP4 Met41 and Ser54 side chains are shown in black. The phenyl group attached to the triazole in this ligand class pushes Met41 into another preferred rotamer that requires Ser54 to also adopt another conformation (arrows). The pKa value of the heterocycle is calculated as 6.6 and it forms three hydrogen bonds to Arg107, Arg127 and Tyr129. This compound is active on hFABP4 with an IC50 of 61 nM, but inhibits hFABP3 only weakly (IC50 of 8.7 µM). The selectivity of this compound class against hFABP3 is ensured by stereochemical conflict with the side chain of Leu116 (red dashes). (c, d) The binding of the U-shaped sulfonamides is different from that of carboxylic acids and varies with compound. Some interactions with Arg107, Arg127 and Tyr129 are water-mediated. |
![[Figure 11]](gm5114fig11.jpg)
 | STRUCTURAL BIOLOGY |
ISSN: 2059-7983
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