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.