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

被引：71

作者：

Hertzel, Ann V. ^{[1
]}

Hellberg, Kristina ^{[1
]}

Reynolds, Joseph M. ^{[2
]}

Kruse, Andrew C. ^{[1
]}

Juhlmann, Brittany E. ^{[1
]}

Smith, Anne J. ^{[1
]}

Sanders, Mark A. ^{[3
]}

Ohlendorf, Douglas H. ^{[1
]}

Suttles, Jill ^{[2
]}

Bernlohr, David A. ^{[1
]}

机构：

[1] Univ Minnesota, Dept Biochem Mol Biol & Biophys, 6-155 Jackson Hall,321 Church St SE, Minneapolis, MN 55455 USA

[2] Univ Louisville, Sch Med, Dept Microbiol & Immunol, Louisville, KY 40292 USA

[3] Univ Minnesota, Imaging Ctr, Minneapolis, MN 55455 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 19期

关键词：

HORMONE-SENSITIVE LIPASE; ACTIVATED RECEPTOR-GAMMA; AP2; METABOLISM; EXPRESSION; OBESITY;

D O I：

10.1021/jm900720m

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-aminonaphthalene 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 PPAR gamma in macrophage or CV-1 cells. These results identify 1 as all inhibitor of fatty acid binding and a competitive antagonist of protein-protein interactions mediated by AFABP/aP2.

引用

页码：6024 / 6031

页数：8

共 43 条

[1] Adipocyte-type fatty acid-binding protein as inter-compartmental shuttle for peroxisome proliferator activated receptor γ agonists in cultured cell [J].

Adida, A ;

Spener, F .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 2006, 1761 (02) :172-181

[2]

[Anonymous], PYMOL MOL GRAPHICS S

[3] Continuous nucleocytoplasmic shuttling underlies transcriptional activation of PPARγ by FABP4 [J].

Ayers, Stephen D. ;

Nedrow, Katherine L. ;

Gillilan, Richard E. ;

Noy, Noa .

BIOCHEMISTRY, 2007, 46 (23) :6744-6752

[4] Investigation of in vivo fatty acid metabolism in AFABP/aP2-/- mice [J].

Baar, RA ;

Dingfelder, CS ;

Smith, LA ;

Bernlohr, DA ;

Wu, CD ;

Lange, AJ ;

Parks, EJ .

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2005, 288 (01) :E187-E193

[5] THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].

BAILEY, S .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763

[6] STRUCTURAL AND FUNCTIONAL-CHARACTERIZATION OF THE PHOSPHORYLATED ADIPOCYTE LIPID-BINDING PROTEIN (PP15) [J].

BUELT, MK ;

XU, ZH ;

BANASZAK, LJ ;

BERNLOHR, DA .

BIOCHEMISTRY, 1992, 31 (13) :3493-3499

[7] The multigene family of fatty acid-binding proteins (FABPs): Function, structure and polymorphism [J].

Chmurzynska, A .

JOURNAL OF APPLIED GENETICS, 2006, 47 (01) :39-48

[8]

Coe NR, 1999, J LIPID RES, V40, P967

[9] CASTp: computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues [J].

Dundas, Joe ;

Ouyang, Zheng ;

Tseng, Jeffery ;

Binkowski, Andrew ;

Turpaz, Yaron ;

Liang, Jie .

NUCLEIC ACIDS RESEARCH, 2006, 34 :W116-W118

[10] Coot:: model-building tools for molecular graphics [J].

Emsley, P ;

Cowtan, K .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2004, 60 :2126-2132

← 1 2 3 4 5 →