G-protein coupled receptors (GPCRs), also known as seven transmembrane (7TM) receptors, are essential for extracellular signals to transduce across the plasma membrane. More than 800 genes in the human genome encode GPCRs, representing the most diverse membrane protein superfamily. Physiologically, GPCRs participate in cellular regulation and can also be related to disease pathogenesis, making them attractive drug targets. As of 2017, around 34% of the drugs approved by the US Food and Drug Administration (FDA) target GPCRs. Understanding the structural details of ligand and transducer interactions with GPCRs and relationship between GPCR structures, GPCR activation, signaling and physiological functions are crucial to understand how they function at the molecular level, and this is of considerable value to enable the design better drugs in the future.
Since 2017, a revolution in GPCR structural biology has been ignited by the use of cryo-electron microscopy (cryo-EM). Breakthroughs in both the hardware and software, including the commercialization of direct electron detectors and the innovation of cryo-EM data analysis packages, has facilitated crystallization-free high-resolution GPCR structure determination, particularly for the active G protein bound GPCR state. In the first half of 2021, 78% of the 99 deposited GPCR structures in the PDB were determined by cryo-EM. The glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are both class B1 GPCR that bind incretin hormones and control the post-prandial insulin secretion and glycemic homeostasis. The surpassing effects in glycemic control and weight loss of tirzepatide (Mounjaro®), a recently FDA-approved dual-agonist on GLP-1R and GIPR, over clinically used GLP-1R agonists attract great interests in both academia and industries. My study aims to determine the Cryo-EM structures of dual-agonist-bound GLP-1R/Gs and GIPR/Gs complexes, together with the profiling of G-protein activation induced by these dual-agonists on both receptors.