Genetics, Bioinformatics, and Computational Biology Program, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
J Mol Model. 2011 Mar;17(3):543-53. doi: 10.1007/s00894-010-0748-y. Epub 2010 May 30.
The rates of type 2 diabetes (T2D) are rising to epidemic proportions in the US and worldwide. While current T2D medications are efficacious, significant side effects have limited their use and availability. Our laboratory has discovered that abscisic acid (ABA) exerts anti-diabetic effects, in part, by activating peroxisome proliferator-activated receptor γ (PPAR γ). However, since ABA does not bind to the ligand-binding domain (LBD) of PPAR γ, the mechanism of activation of PPAR γ by ABA remains unknown. Lanthionine synthetase component C-like protein 2 (LANCL2) was predicted to be a novel target for the binding and signaling of ABA in human granulocytes and rat insulinoma cells. The goal of this study was to determine whether LANCL2 is a molecular target of ABA and other PPAR γ agonists. To this end we performed homology modeling to construct a three-dimensional structure of LANCL2 using the crystal structure of LANCL1 as a template. Our molecular docking studies predicted that ABA and other PPAR γ agonists (e.g., rosiglitazone and pioglitazone) share a binding site on the surface of LANCL2. The identification of a binding site for PPAR γ agonists will facilitate the high-throughput virtual screening of large compound libraries and may shed new light on alternative mechanisms of PPAR γ activation.
在美国和全球范围内，2 型糖尿病（T2D）的发病率正在上升到流行的程度。虽然目前的 T2D 药物是有效的，但严重的副作用限制了它们的使用和可用性。我们的实验室发现，脱落酸（ABA）通过激活过氧化物酶体增殖物激活受体 γ（PPAR γ）发挥抗糖尿病作用。然而，由于 ABA 不与 PPAR γ 的配体结合域（LBD）结合，因此 ABA 激活 PPAR γ 的机制尚不清楚。硫胺素合成酶成分 C 样蛋白 2（LANCL2）被预测为 ABA 及其它 PPAR γ 激动剂在人嗜中性粒细胞和大鼠胰岛素瘤细胞中结合和信号转导的新靶标。本研究的目的是确定 LANCL2 是否是 ABA 和其它 PPAR γ 激动剂的分子靶标。为此，我们进行了同源建模，使用 LANCL1 的晶体结构作为模板构建了 LANCL2 的三维结构。我们的分子对接研究预测 ABA 和其它 PPAR γ 激动剂（如罗格列酮和吡格列酮）在 LANCL2 的表面共享一个结合位点。鉴定 PPAR γ 激动剂的结合位点将有助于高通量虚拟筛选大型化合物库，并可能为 PPAR γ 激活的替代机制提供新的线索。
