The long-term objectives of this project are to unravel the structural basis of hormone binding and activation of the family of Class B G-protein-coupled receptors (GPCRs) and to explore the obtained structural information with a goal toward rational design of peptide hormones to treat human diseases. The secretin family of Class B GPCRs consists of 15 members in humans, including receptors for parathyroid hormone (PTH), glucagon (GCG), glucagon-like-peptide-1 (GLP1), and corticotropin-releasing factor (CRF). These peptide hormones are known to play crucial roles in metabolic homeostasis and the integrity of skeleton systems. As such, Class B GPCRs are well-established drug targets. A PTH fragment (residues 1-34) and a GLP1 analog (exendin-4, isolated from lizard venom) have been used for the treatment of osteoporosis and type II diabetes. However, the clinical use of these peptide analogs is limited by side effects, partly associated with their low receptor binding affinity or low pharmacological stability. The discovery of highly potent and selective ligands for Class B GPCRs remains an important goal of pharmaceutical research. The Class B GPCR contains an N-terminal extracellular domain (ECD) that is responsible for specific hormone recognition. As such the ECD has been the focus of intense structural study. Until recently, structure solution of a receptor ECD/hormone complex has been hindered by technical difficulties. This limited structural information is a serious deficiency considering the importance of Class B GPCRs and their hormones in normal physiology and in disease. In this study, we propose to fill this knowledge gap by solving the crystal structures of several therapeutically important Class B GPCR ECDs bound to their corresponding peptide hormones.
Our specific aims are focused on structural determination of the ECD of PTH1R and PTH2R bound to PTH, PTHrP, and TIP39. After structural determination, we will scrutinize and analyze the structures for key structural elements, and we will assess the functional significance of those elements by site-directed mutagenesis and biochemical binding assays. These studies will provide the molecular basis of hormone recognition and a rational template for drug discovery. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page Program Director/Principal Investigator (Last, First, Middle): Xu, H. Eric
to Human Health The Class B GPCRs for PTH, CRF, GLP1, and glucagon are important drug targets for osteoporosis, depression, and diabetes, which are becoming major diseases for aging Americans. Crystal structures of these receptors bound to their respective peptide hormones will not only provide a molecular basis of hormone recognition, but also a rational template for drug design targeting these receptors.
| He, Yuanzheng; Gao, Xiang; Goswami, Devrishi et al. (2017) Molecular assembly of rhodopsin with G protein-coupled receptor kinases. Cell Res 27:728-747 |
| Zhou, X Edward; He, Yuanzheng; de Waal, Parker W et al. (2017) Identification of Phosphorylation Codes for Arrestin Recruitment by G Protein-Coupled Receptors. Cell 170:457-469.e13 |
| Kang, Yanyong; Gao, Xiang; Zhou, X Edward et al. (2016) A structural snapshot of the rhodopsin-arrestin complex. FEBS J 283:816-21 |
| Kang, Yanyong; Zhou, X Edward; Gao, Xiang et al. (2015) Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature 523:561-7 |
| Joiner, Danese M; Ke, Jiyuan; Zhong, Zhendong et al. (2013) LRP5 and LRP6 in development and disease. Trends Endocrinol Metab 24:31-9 |
| Ke, Jiyuan; Xu, H Eric; Williams, Bart O (2013) Lipid modification in Wnt structure and function. Curr Opin Lipidol 24:129-33 |
| Ke, Jiyuan; Zhang, Chenghai; Harikumar, Kaleeckal G et al. (2012) Modulation of ?-catenin signaling by glucagon receptor activation. PLoS One 7:e33676 |
| Pal, Kuntal; Melcher, Karsten; Xu, H Eric (2012) Structure and mechanism for recognition of peptide hormones by Class B G-protein-coupled receptors. Acta Pharmacol Sin 33:300-11 |
| Zhou, X Edward; Melcher, Karsten; Xu, H Eric (2012) Structure and activation of rhodopsin. Acta Pharmacol Sin 33:291-9 |
| Pal, Kuntal; Swaminathan, Kunchithapadam; Xu, H Eric et al. (2010) Structural basis for hormone recognition by the Human CRFR2{alpha} G protein-coupled receptor. J Biol Chem 285:40351-61 |
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