The human calcitonin receptor (CTR) is a G protein-coupled receptor that is an important drug target because of its role in mediating the distinct biological actions of two related endocrine peptide hormones, calcitonin (CT) and amylin (AMY). CT regulates calcium homeostasis and bone turnover by signaling through the CTR. AMY regulates blood glucose levels by signaling through a heterodimeric complex ofthe CTR and any one of three related receptor activity modifying proteins (RAMPs) that act as co-receptors to alter CTR specificity for AMY. Agonism of the CT and AMY receptors by synthetic analogs of the hormones is used to treat osteoporosis and types I and II diabetes, respectively. Despite the clinical value of CT and AMY receptor agonism, the molecular mechanisms of CTR hormone binding and RAMP-mediated alteration of CTR hormone specificity are poorly understood because of a lack of structural information for the hormone-receptor complexes. CT and AMY binding affinity and specificity are in large part determined by the extracellular domains (ECDs) ofthe CTR and RAMP integral membrane proteins. The goals of this proposal are to characterize the hormone-receptor ECD interactions and to determine crystal structures of soluble CT- and AMY-receptor ECD complexes. The results will define the molecular bases for CT and AMY binding to their receptor ECDs, delineate how RAMPs alter hormone specificity ofthe CTR, and provide structural templates to guide the design of optimized therapeutics targeting the receptors. We propose the following three aims: (1) Determine the molecular mechanism of CT recognition by the human CTR ECD. The crystal structures generated in this aim will define how human and salmon CT hormones bind to the CTR and aid the development of therapeutics for treating osteoporosis. (2) Determine the structural and functional bases for interaction ofthe CTR and RAMP ECDs. The resulting CTR ECD-RAMP ECD heterodimer structure will reveal the molecular architecture of an AMY receptor. (3) Determine the molecular mechanism of AMY binding to a CTR ECD-RAMP ECD heterodimer. Achieving this aim will define how a RAMP alters the hormone specificity of the CTR and aid the design of therapeutics for diabetes.

Public Health Relevance

The goal of this proposal is to determine the molecular mechanisms by which the hormones calcitonin and amylin are recognized by their cell surface G protein-coupled receptors. Analogs of calcitonin and amylin are used to treat osteoporosis and types I and II diabetes, respectively. Obtaining a detailed biochemical description of how these hormones bind to their receptors will facilitate the rational development of potent and selective next-generation therapeutic agents for the treatment of osteoporosis and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103640-02
Application #
8518425
Study Section
Special Emphasis Panel (ZRR1-RI-B)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$233,829
Indirect Cost
Name
University of Oklahoma Norman
Department
Type
DUNS #
848348348
City
Norman
State
OK
Country
United States
Zip Code
73019
Hebdon, Skyler D; Menon, Smita K; Richter-Addo, George B et al. (2018) Regulatory Targets of the Response Regulator RR_1586 from Clostridioides difficile Identified Using a Bacterial One-Hybrid Screen. J Bacteriol 200:
Cruz-Reyes, Jorge; Mooers, Blaine H M; Doharey, Pawan K et al. (2018) Dynamic RNA holo-editosomes with subcomplex variants: Insights into the control of trypanosome editing. Wiley Interdiscip Rev RNA 9:e1502
Booe, Jason M; Warner, Margaret L; Roehrkasse, Amanda M et al. (2018) Probing the Mechanism of Receptor Activity-Modifying Protein Modulation of GPCR Ligand Selectivity through Rational Design of Potent Adrenomedullin and Calcitonin Gene-Related Peptide Antagonists. Mol Pharmacol 93:355-367
Muthuramalingam, Meenakumari; White, John C; Murphy, Tamiko et al. (2018) The toxin from a ParDE toxin-antitoxin system found in Pseudomonas aeruginosa offers protection to cells challenged with anti-gyrase antibiotics. Mol Microbiol :
Roehrkasse, Amanda M; Booe, Jason M; Lee, Sang-Min et al. (2018) Structure-function analyses reveal a triple ?-turn receptor-bound conformation of adrenomedullin 2/intermedin and enable peptide antagonist design. J Biol Chem 293:15840-15854
Van Orden, Mason J; Klein, Peter; Babu, Kesavan et al. (2017) Conserved DNA motifs in the type II-A CRISPR leader region. PeerJ 5:e3161
Murugan, Karthik; Babu, Kesavan; Sundaresan, Ramya et al. (2017) The Revolution Continues: Newly Discovered Systems Expand the CRISPR-Cas Toolkit. Mol Cell 68:15-25
Li, Yangxiong; Lavey, Nathan P; Coker, Jesse A et al. (2017) Consequences of Depsipeptide Substitution on the ClpP Activation Activity of Antibacterial Acyldepsipeptides. ACS Med Chem Lett 8:1171-1176
Wang, Bing; Powell, Samantha M; Guan, Ye et al. (2017) Nitrosoamphetamine binding to myoglobin and hemoglobin: Crystal structure of the H64A myoglobin-nitrosoamphetamine adduct. Nitric Oxide 67:26-29
Sundaresan, Ramya; Parameshwaran, Hari Priya; Yogesha, S D et al. (2017) RNA-Independent DNA Cleavage Activities of Cas9 and Cas12a. Cell Rep 21:3728-3739

Showing the most recent 10 out of 47 publications