Characterisation of the Z-pocket for the treatment of alpha-1-antitrypsin deficiency

α-1-抗胰蛋白酶(A1AT)缺乏是一种相对常见的遗传性疾病，会导致肺和肝脏疾病，如肺气肿、肝硬变和癌症。目前还没有治愈或治疗的方法。最常见的原因是Z突变，它导致错误折叠的A1AT‘聚合体’在肝细胞中积累。作为之前MRC资助的一部分，我们发现了Z-A1AT聚合的一种令人惊讶的机制，以及导致Z-A1AT错误折叠的结构特征。目前这项研究的目标是更详细地研究我们命名为Z-Pocket的这一特征。与Z-口袋结合的化合物可以挽救Z-A1AT的折叠，有效地治愈疾病。我们将使用X射线结晶学和核磁共振来确定Z口袋的性质，并看看以前发现的化合物是否通过填充口袋来挽救折叠。该项目的成功完成将为发现治疗A1AT缺乏症的新药奠定基础。

Alpha-1-antitrypsin (a1AT) deficiency is a relatively common genetic disorder resulting in lung and liver diseases, such as emphysema, cirrhosis and cancer. There is currently no cure or treatment. The most common cause is the 'Z' mutation which leads to the accumulation of misfolded a1AT 'polymers' in liver cells. As part of a previous MRC grant, we discovered a surprising mechanism of Z-a1AT polymerization and the structural feature that causes Z-a1AT to misfold. The goal of the current research is to study the feature, that we named the 'Z-pocket', in more detail. Compounds that bind to the Z-pocket could rescue the folding of Z-a1AT and effectively cure the disease. We will use X-ray crystallography and nuclear magnetic resonance to determine the properties of the Z-pocket and to see if previously identified compounds rescue folding by filling the pocket. Successful completion of this project will set the stage for the discovery of new drugs for the treatment of a1AT-deficiency.