Wagner Armin, Diez Joachim, Schulze-Briese Clemens, Schluckebier Gerd
Swiss Light Source, Paul Scherrer Institute, CH-5323 Villigen PSI, Switzerland.
Proteins. 2009 Mar;74(4):1018-27. doi: 10.1002/prot.22213.
Ultralente insulin has been one of the commercially most important insulin preparations in diabetes treatment over the last 50 years. It is a suspension of insulin microcrystals which dissolve slowly following subcutaneous injection. Because of the small crystal size of about 25 x 25 x 5 microm(3) the atomic structure has been elusive until now. Here we present the crystal structures from Ultralente and their precursor microcrystals from the industrial manufacturing process. During this process insulin undergoes a conformational change within the microcrystals. Both structures show canonical folding of the insulin molecules but exhibit a number of new features when compared with other insulin structures. Surprisingly, we found that the Ultralente crystals bind the conservation agent methylparaben, which slows down dissolution of the crystals and thus contributes to the long duration of action.
在过去50年里，超长效胰岛素一直是糖尿病治疗中商业上最重要的胰岛素制剂之一。它是胰岛素微晶的混悬液，皮下注射后会缓慢溶解。由于晶体尺寸小，约为25×25×5微米³，其原子结构至今仍难以捉摸。在此，我们展示了超长效胰岛素及其工业制造过程中前体微晶的晶体结构。在此过程中，胰岛素在微晶内发生构象变化。两种结构均显示胰岛素分子的典型折叠，但与其他胰岛素结构相比呈现出一些新特征。令人惊讶的是，我们发现超长效胰岛素晶体结合了防腐剂对羟基苯甲酸甲酯，这减缓了晶体的溶解，从而有助于延长作用持续时间。
