Education:
- PhD, University of Michigan 2003
Clinical/Research Interests:
Structural biology of cell surface receptors and their ligands; molecular mechanisms of G protein-coupled receptor signaling; structure-based development of therapeutic agents.
Our research is aimed at understanding the structure and function of cell surface receptor/ligand complexes involved in clinically important cellular signaling pathways. We are currently 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 various 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. Despite their physiological and clinical importance, many questions about GPCR structure and function remain unanswered. 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 additional regulatory proteins interact with the receptors and modulate their function? Can structural information be used to guide the development of novel GPCR drugs?
To tackle these questions we use a multi-disciplinary approach employing the tools of structural biology, biochemistry, pharmacology, and cell biology. Our current goals are centered on structure/function studies of a subset of GPCRs known as class B receptors. This family of GPCRs includes the receptors for the calcitonin 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 five areas: (a) expression and purification of soluble domains of the receptors, (b) expression and purification of full-length receptors and their complexes with transducer proteins, (c) structural studies of receptor/ligand complexes, (d) functional studies of the receptors using purified protein and cell-based assays, and (e) 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 osteoporosis, diabetes, cardiovascular disorders, and cancer.
Our research on class B GPCRs is currently supported by NIH National Institute of General Medical Sciences award R01GM104251.
Select Publications:
- 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. Epub ahead of print.
- Booe, J. M., Warner, M. L., Roehrkasse, A. M., Hay, D. L., and Pioszak, A. A. (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(4), 355-67.
- Lee, S-M., Booe, J. M., Gingell, J. J., Sjoelund, V., Hay, D. L., and Pioszak, A. A. (2017). N-glycosylation of asparagine 130 in the extracellular domain of the human calcitonin receptor significantly increases peptide hormone affinity. Biochemistry. 56(26), 3380-93.
- Lee, S-M., Hay, D. L., and Pioszak, A. A. (2016).Calcitonin and amylin receptor peptide interaction mechanisms:Insights into peptide-binding modes and allosteric modulation of the calcitonin receptor by receptor activity-modifying proteins.J. Biol. Chem. 291, 8686-700.
- Hay, D. L. and Pioszak, A. A. (2016). Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles. Annu Rev Pharmacol Toxicol. 56, 469-87.
- Booe, J. M., Walker, C. S., 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.
- Lee, S-M., Booe, J. M., and Pioszak, A. A. (2015). Structural insights into ligand recognition and selectivity for classes A, B, and C GPCRs. Eur J Pharmacol. 763, 196-205.
- Warner, M. L, Bell, T., and Pioszak, A. A. (2015). Engineering high-potency R-spondin adult stem cell growth factors. Mol Pharmacol. 87, 410-420.
- Moad, H. E., and Pioszak, A. A. (2013). Selective CGRP and adrenomedullin peptide binding by tethered RAMP-calcitonin receptor-like receptor extracellular domain fusion proteins. Protein Sci. 22, 1775-85.
- Moad, H. E., and Pioszak, A. A. (2013). Reconstitution of R-spondin:LGR4:ZNRF3 adult stem cell growth factor signaling complexes with recombinant proteins produced in Escherichia coli. Biochemistry. 52(41), 7295-304.
- Hill, H. E., and Pioszak, A. A. (2013). Bacterial expression and purification of a heterodimeric adrenomedullin receptor extracellular domain complex using DsbC-assisted disulfide shuffling. Protein Expr Purif. 88(1), 107-113.
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