3HK1

Identification and Characterization of a Small Molecule Inhibitor of Fatty Acid Binding Proteins

3HK1 の概要

• エントリーDOI: 10.2210/pdb3hk1/pdb
• 分子名称: Fatty acid-binding protein, adipocyte, 4-{[2-(methoxycarbonyl)-5-(2-thienyl)-3-thienyl]amino}-4-oxo-2-butenoic acid (3 entities in total)
• 機能のキーワード: lipid binding protein, fatty acid binding protein, cytoplasm, lipid-binding, nucleus, phosphoprotein, transport, protein binding
• 由来する生物種: Mus musculus (mouse)
• 細胞内の位置: Cytoplasm: P04117
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 14877.06

構造登録者

Hertzel, A.V.,Hellberg, K.,Reynolds, J.M.,Kruse, A.C.,Juhlmann, B.E.,Smith, A.J.,Sanders, M.A.,Ohlendorf, D.H.,Suttles, J.,Bernlohr, D.A. (登録日: 2009-05-22, 公開日: 2009-09-22, 最終更新日: 2023-09-06)

主引用文献

Hertzel, A.V.,Hellberg, K.,Reynolds, J.M.,Kruse, A.C.,Juhlmann, B.E.,Smith, A.J.,Sanders, M.A.,Ohlendorf, D.H.,Suttles, J.,Bernlohr, D.A.
Identification and characterization of a small molecule inhibitor of Fatty Acid binding proteins.
J.Med.Chem., 52:6024-6031, 2009

PubMed Abstract: Molecular disruption of the lipid carrier AFABP/aP2 in mice results in improved insulin sensitivity and protection from atherosclerosis. Because small molecule inhibitors may be efficacious in defining the mechanism(s) of AFABP/aP2 action, a chemical library was screened and identified 1 (HTS01037) as a pharmacologic ligand capable of displacing the fluorophore 1-anilinonaphthalene 8-sulfonic acid from the lipid binding cavity. The X-ray crystal structure of 1 bound to AFABP/aP2 revealed that the ligand binds at a structurally similar position to a long-chain fatty acid. Similar to AFABP/aP2 knockout mice, 1 inhibits lipolysis in 3T3-L1 adipocytes and reduces LPS-stimulated inflammation in cultured macrophages. 1 acts as an antagonist of the protein-protein interaction between AFABP/aP2 and hormone sensitive lipase but does not activate PPARgamma in macrophage or CV-1 cells. These results identify 1 as an inhibitor of fatty acid binding and a competitive antagonist of protein-protein interactions mediated by AFABP/aP2.

PubMed: 19754198
DOI: 10.1021/jm900720m

実験手法

X-RAY DIFFRACTION (1.7 Å)