Rufer Arne C, Thoma Ralf, Benz Jörg, Stihle Martine, Gsell Bernard, De Roo Elodie, Banner David W, Mueller Francis, Chomienne Odile, Hennig Michael
F. Hoffmann-La Roche AG, Pharma Research Discovery, 4070 Basel, Switzerland.
Structure. 2006 Apr;14(4):713-23. doi: 10.1016/j.str.2006.01.008.
Carnitine palmitoyltransferases 1 and 2 (CPTs) facilitate the import of long-chain fatty acids into mitochondria. Modulation of the catalytic activity of the CPT system is currently under investigation for the development of novel drugs against diabetes mellitus. We report here the 1.6 A resolution structure of the full-length mitochondrial membrane protein CPT-2. The structure of CPT-2 in complex with the generic CPT inhibitor ST1326 ([R]-N-[tetradecylcarbamoyl]-aminocarnitine), a substrate analog mimicking palmitoylcarnitine and currently in clinical trials for diabetes mellitus treatment, was solved at 2.5 A resolution. These structures of CPT-2 provide insight into the function of residues involved in substrate binding and determination of substrate specificity, thereby facilitating the rational design of antidiabetic drugs. We identify a sequence insertion found in CPT-2 that mediates membrane localization. Mapping of mutations described for CPT-2 deficiency, a hereditary disorder of lipid metabolism, implies effects on substrate recognition and structural integrity of CPT-2.
肉碱棕榈酰转移酶1和2（CPTs）促进长链脂肪酸进入线粒体。目前正在研究CPT系统催化活性的调节，以开发抗糖尿病的新型药物。我们在此报告全长线粒体膜蛋白CPT-2的1.6埃分辨率结构。CPT-2与通用CPT抑制剂ST1326（[R]-N-[十四烷基氨基甲酰基]-氨基肉碱）（一种模拟棕榈酰肉碱的底物类似物，目前正处于糖尿病治疗的临床试验阶段）形成复合物的结构在2.5埃分辨率下得到解析。CPT-2的这些结构有助于深入了解参与底物结合的残基的功能以及底物特异性的确定，从而促进抗糖尿病药物的合理设计。我们鉴定出CPT-2中一个介导膜定位的序列插入。对CPT-2缺乏症（一种脂质代谢遗传性疾病）所描述的突变进行定位，表明其对CPT-2的底物识别和结构完整性有影响。
