Structural approach to correcting an abnormal servomechanism involved in appetite regulation

Structural approach to correcting an abnormal servomechanism involved in appetite regulation Structural approach to correcting an abnormal servomechanism involved in appetite regulation Obesity and metabolic syndromes are epidemic in the United States and across the world, contributing to a similar increase in diabetes and associated co-morbidities. The gastrointestinal hormone, cholecystokinin (CCK) has been recognized as an important regulator of post-cibal satiety, yet this servomechanism is dysfunctional in a subset of patients with these diseases. A key contributor to this dysfunction is membrane cholesterol, altering the microenvironment of the type 1 CCK receptor (CCK1R). In this project, we will gain insights into this abnormal conformation of CCK1R by determining the crystal structure of a stable surrogate, CCK1R(Y140A), which mimics the dysfunction of this receptor in elevated cholesterol. This study will provide critical structural information that could be utilized for in silico screening of drug candidates, with iterative testing and refinement in an in vitro cell culture model. The best candidates will ultimately be tested in pre-clinical and clinical studies.