Medicinal chemist Chris de Graaf in Nature with 3D structures of diabetes drug targets

Chris de Graaf (Medicinal Chemistry) participated in international research teams that solved the three-dimensional structures of two drug targets for Type 2 diabetes, the glucagon-like peptide 1 receptor (GLP-1R) and the glucagon receptor (GCGR). Last week, the results of these studies were published in two complementary articles in Nature.

05/24/2017 | 4:50 PM

The international research teams, including scientists from China, United States, Denmark, and AIMMS report on the first 3D structures of the transmembrane domain of the glucagon-like peptide 1 receptor (GLP-1R) and the first full-length structures of the glucagon receptor (GCGR). These two transmembrane G-protein-coupled receptors (GPCRs) play opposing key roles in glucose homeostasis and serve as important drug targets for Type 2 diabetes. The combined studies provide new opportunities to design synergistic therapeutic strategies involving both GCGR and GLP1R for Type 2 diabetes.

Full structural picture of receptor function

One of the Nature publications presents the first full-length GCGR structure in complex with a monoclonal antibody that interacts with the extracellular domain (ECD) and a negative allosteric modulator molecule that binds the transmembrane domain of the receptor. Both domains are required to interact with the glucagon hormone and to regulate downstream signal transduction, but until now structures of complete, full-length class B GPCRs remained elusive. The high resolution X-ray crystal structure, complemented by hydrogen-deuterium exchange mass spectrometry, disulfide cross-linking, molecular pharmacology studies, and molecular simulation studies provide surprising new insights into the structural molecular mechanisms that regulate peptide binding to these pharmaceutically relevant receptors.

Binding pockets for negative and positive receptor modulation

The second Nature publication presents the first structures of GLP-1R in complex with two negative allosteric modulators (NAMs) that lock the receptor in an inactive conformation by targeting a binding pocket located at the receptor-membrane interface, that is also present in GCGR. Mutagenesis and molecular simulation studies indicate that positive allosteric modulators (PAMs) target the same general region, but in a distinct sub-pocket, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling.

De_Graaf_Nature_1 De_Graaf_Nature_2

Figures via iHuman/SIMM