The majority of hormones and neurotransmitters communicate information to cells via G protein-coupled receptors (GPCRs), and GPCRs represent the largest group of targets for drug development. My laboratory has a long-standing interest in elucidating the structure and mechanism of action of GPCRs using the 132 adrenoceptor ([52AR) as a model system. The 15_AR responds to the catecholamine neurotransmitters epinephrine, norepinephrine and dopamine. It has been one of the most extensively characterized members of the GPCR family, and much is known about its agonist binding and G protein coupling domains from extensive mutagenesis studies. My lab has developed approaches to monitor directly ligand-induced conformational changes in purified [52AR protein. Our experiments reveal that the [52AR is a dynamic molecule with complex behavior. We found that agonists and partial agonists induce ligand-specific conformational states, and that agonist activation proceeds through intermediate conformational states. The studies outlined in this proposal will extend these observations by obtaining a high-resolution three-dimensional structure of the beta2AR;by characterizing the dynamic properties of the 7TM segments of the beta2AR;and by mapping the structural changes induced by different classes of ligands (agonists, partial agonists, neutral antagonists, and inverse agonists). Many of the findings will apply to the large number of closely related monoamine receptors and to GPCRs in general. Moreover, the methodologies developed for characterizing [52AR structure will likely be applicable to other GPCRs. A better understanding of the three-dimensional structure and mechanism of activation of GPCRs will further the potential of structure-based drug design and in silico screening for GPCR targets, leading to more rapid development of highly selective and effective drugs.
| Liu, Xiangyu; Ahn, Seungkirl; Kahsai, Alem W et al. (2017) Mechanism of intracellular allosteric ?2AR antagonist revealed by X-ray crystal structure. Nature 548:480-484 |
| Staus, Dean P; Strachan, Ryan T; Manglik, Aashish et al. (2016) Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation. Nature 535:448-52 |
| Shukla, Arun K; Westfield, Gerwin H; Xiao, Kunhong et al. (2014) Visualization of arrestin recruitment by a G-protein-coupled receptor. Nature 512:218-222 |
| Ring, Aaron M; Manglik, Aashish; Kruse, Andrew C et al. (2013) Adrenaline-activated structure of ?2-adrenoceptor stabilized by an engineered nanobody. Nature 502:575-579 |
| Shukla, Arun K; Manglik, Aashish; Kruse, Andrew C et al. (2013) Structure of active ?-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature 497:137-41 |
| Kruse, Andrew C; Manglik, Aashish; Kobilka, Brian K et al. (2013) Applications of molecular replacement to G protein-coupled receptors. Acta Crystallogr D Biol Crystallogr 69:2287-92 |
| Nygaard, Rie; Zou, Yaozhong; Dror, Ron O et al. (2013) The dynamic process of ?(2)-adrenergic receptor activation. Cell 152:532-42 |
| Chae, Pil Seok; Kruse, Andrew C; Gotfryd, Kamil et al. (2013) Novel tripod amphiphiles for membrane protein analysis. Chemistry 19:15645-51 |
| Kruse, Andrew C; Hu, Jianxin; Pan, Albert C et al. (2012) Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature 482:552-6 |
| Manglik, Aashish; Kruse, Andrew C; Kobilka, Tong Sun et al. (2012) Crystal structure of the ยต-opioid receptor bound to a morphinan antagonist. Nature 485:321-6 |
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