Education:
- PhD, University of Michigan 2003
Clinical/Research Interests:
Molecular mechanisms of G protein-coupled receptor signaling; structural biology; structure-based development of therapeutic agents.
Our research seeks to understand the structure and function of cell surface receptor/ligand complexes involved in clinically important cellular signaling pathways. We are focused on G protein-coupled receptors (GPCRs), a class of proteins that are responsible for mediating the actions of many peptide and protein hormones, neurotransmitters, and numerous other bioactive molecules. GPCRs constitute the largest family of cell surface signaling proteins in the human genome and they are among the most successful targets for therapeutic intervention with about 30% of drugs on the market targeting GPCRs. Some of the questions we are working to answer include: How do endogenous ligands and drugs bind to the receptors and how is specificity/selectivity achieved? How are signals transmitted across the membrane to various transducer proteins? How do regulatory proteins interact with the receptors and modulate their functions? How do different ligands elicit distinct downstream signaling outcomes? Can we rationally engineer novel GPCR ligands tailored to yield desired therapeutic outcomes?
To tackle these questions we use a multi-disciplinary approach employing the tools of biochemistry, biophysics, pharmacology, structural biology, and cell biology. Our current goals are centered on studies of a subset of GPCRs known as class B receptors. This family includes the receptors for the calcitonin/CGRP family peptides, parathyroid hormone, glucagon, corticotropin releasing factor, and several other clinically important endocrine hormones, autocrine/paracrine factors, and neuropeptides. Our efforts are focused on the following areas: (a) functional studies of the receptors using purified protein and various cell-based assays (b) expression and purification of the receptors and their complexes with transducer proteins, (c) structural studies of receptor complexes, and (d) using the knowledge gained from our studies to engineer novel pharmacological tools and therapeutic agents. Ultimately, we hope that our research will lead to new therapeutic options for the treatment of diseases including diabetes, obesity, cardiovascular disorders, and cancer.
Select Publications:
- Babin, K. M., Gostynska, S. E., Karim, J. A., and Pioszak, A. A. (2024). Variable CGRP family peptide signaling durations and the structural determinants thereof. Biochem Pharmacol. 224, 116235.
- Babin, K. M., Karim, J. A., Gordon, P. H., Lennon, J., Dickson, A., and Pioszak, A. A. (2023). Adrenomedullin 2/intermedin is a slow off-rate, long-acting endogenous agonist of the adrenomedullin2 G protein-coupled receptor. J Biol Chem. 299, 104785.
- Booe, J. M., Warner, M. L, and Pioszak, A. A. (2020). Picomolar affinity antagonist and sustained signaling agonist peptide ligands for the adrenomedullin and calcitonin gene-related peptide receptors. ACS Pharmacol Transl Sci. 3, 759-772.
- Roehrkasse, A. M., Warner, M. L., Booe, J. M., and Pioszak, A. A. (2020). Biochemical characterization of G protein coupling to calcitonin gene-related peptide and adrenomedullin receptors using a native PAGE assay. J Biol Chem. 295(28), 9736-9751.
- Lee, S-M., Jeong, Y., Simms, J., Warner, M. L., Poyner, D. R., Chung, K. Y., and Pioszak, A. A. (2020). Calcitonin receptor N-glycosylation enhances peptide hormone affinity by controlling receptor dynamics. J Mol Biol. 432(7), 1996-2014.
- Roehrkasse, A. M., Booe, J. M., Lee, S-M., Warner, M. L., and Pioszak, A. A. (2018). Structure-function analyses reveal a triple β-turn receptor-bound conformation of adrenomedullin 2/intermedin and enable peptide antagonist design. J Biol Chem. 293(41), 15840-54.
- Booe, J. M., Walker, C., Barwell, J., Kuteyi, G., Simms, J., Jamaluddin, M. A., Warner, M. L., Bill, R. M., Harris, P. W., Brimble, M. A., Poyner, D. R., Hay, D. L., and Pioszak, A. A. (2015). Structural basis for receptor activity-modifying protein-dependent selective peptide recognition by a G protein-coupled receptor. Mol Cell. 58, 1040-52.
Link to full publication list >