阿司匹林及其衍生物与脂肪酸结合蛋白4复合物的晶体学研究

Crystallography study of the complexes of human fatty acid binding protein 4 with aspirin and its derivative

脂肪酸结合蛋白4(Fatty Acid Binding Protein 4,FABP4)作为脂肪酸伴侣,参与调节脂肪酸代谢、运输、脂介导的信号转导以及巨噬细胞的炎症反应。该蛋白的抑制经常作为治疗脂肪代谢疾病的有效方案。本文报道了经典非甾体抗炎药阿司匹林及其水解物水杨酸与FABP4蛋白复合物的晶体结构,从而推测阿司匹林可能通过FABP4蛋白途径抑制动脉粥样硬化的分子机制。结构分析进一步阐明了FABP4蛋白疏水残基Phe16苯环侧链与水杨酸之间的C-H-π相互作用比亲水位点静电相互作用提供更稳定的结合。该发现为设计更高选择性FABP4抑制剂提供了新的途径。

Background： Fatty acid binding protein 4 （FABP4）, as fatty acid chaperone, plays center roles in lipid transport, lipolysis and liposynthesis, and it has been proved to be involved in the lipid signaling and inflammatory responses. Inhibitors of FABP4 are promising treatments for the diabetes and atherosclerosis. Purpose： The aim is to reveal the structural conformation of aspirin and salicylic acid binding to the FABP4, and to explore the novel structural features for the design of high-selective FABP4 inhibitors. Methods： Single crystal X-ray diffraction is applied to solve the structure of the ligand-protein complexes. Results： We have determined the crystal structures of FABP4 in complex with aspirin and its derivative, and from which a special C-H-π interaction between the residues Phe 16, Arg 126 and the benzyl ring of aspirin has been defined. Conclusion： The complex structures of FABP4 bound with aspirin and its derivative show that the edge-to-face C-H-π interaction between the residues Phel6, Arg126 and the benzyl ring of aspirin is a critical intermolecular force between the ligand-FABP4 interactions, which enables us to consciously apply these interactions in hit and lead optimization in rational structure based drug design.