Pioszak, Augen A. PhD

Assistant Professor 


Contact Information:

Office: BRC 462B
Phone: (405) 271-2401
Fax:     (405) 271-3092
 
Mailing Address:
975 N.E. 10th St., BRC462B
Oklahoma City, OK  73104 

augen-pioszak@ouhsc.edu


Education:


PhD, University of Michigan 2003


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 40% of drugs on the market targeting GPCRs.  Despite their physiological and clinical importance, many fundamental questions about GPCR structure and function remain unanswered.  How do endogenous ligands and drugs bind to the receptor and how is specificity/selectivity achieved?  How are signals transduced across the membrane?  How do additional regulatory proteins interact with the receptors and modulate their function?

We use a multi-disciplinary approach to try to answer these questions.  Our primary tool is X-ray crystallography for structural studies, but we also employ the tools of biochemistry, pharmacology, and cell biology for functional studies.  Our current goals are centered on structure/function studies of a subset of GPCRs known as class B receptors.  This class of GPCRs includes the receptors for parathyroid hormone, glucagon, corticotropin releasing factor, and several other clinically important endocrine hormones, autocrine/paracrine factors, and neuropeptides.  Our efforts are focused on four areas:  (a) expression and purification of soluble domains of the receptors, (b) expression and purification of full-length receptors, (c) structural studies of receptor/ligand complexes using X-ray crystallography, and (d) functional studies using purified protein and cell-based assays of receptors in their native membrane environment. Ultimately, we plan to use the knowledge gained from our studies to guide the design of therapeutic agents targeting these receptors for the treatment of diseases including osteoporosis, depression, diabetes, cardiovascular disorders, and cancer.

Our research on class B GPCRs is currently supported by NIH National Institute of General Medical Sciences award 1R01GM104251.

Pioszak CGRP_AMpicture

 

Crystal structures of the extracellular domain heterodimers of the CGRP and Adrenomedullin (AM) receptors with bound peptides.  Receptor activity modifying proteins (RAMPs) determine the ligand selectivity of the class B GPCR calcitonin receptor-like receptor (CLR). 


Selected Publications:

  • Hay, D. L., and Pioszak, A. A. (2015). Receptor acitivty-modifying proteins (RAMPs):  New insights and roles.  Annu Rev Pharmacol Toxicol.  Oct 22, Epub ahead of print.
  • 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.
  • Pal, K., Swaminathan, K., Xu, H. E., and A. A. Pioszak. (2010). Structural basis for hormone recognition by the human CRFR2a G protein-coupled receptor.  J. Biol. Chem. 285, 40351-40361.
  • Pioszak, A. A., Harikumar, K. G., Parker, N. R., Miller, L. J., and H. E. Xu. (2010). Dimeric arrangement of the parathyroid hormone receptor and a structural mechanism for ligand-induced dissociation.  J. Biol. Chem. 285, 12435-12444.  
  • Pioszak, A. A., Parker, N. R., Gardella, T. J., and H. E. Xu. (2009). Structural basis for parathyroid hormone-related protein binding to the parathyroid hormone receptor and design of conformation-selective peptides.  J. Biol. Chem. 284, 28382-28391.  
  • Pioszak, A. A., Parker, N. R., Suino-Powell, K., and H. E. Xu. (2008). Molecular recognition of corticotropin-releasing factor by its G protein-coupled receptor CRFR1. J. Biol. Chem. 283, 32900-32912.  
  • Pioszak, A. A., and H. E. Xu. (2008). Molecular recognition of parathyroid hormone by its G protein-coupled receptor. Proc. Natl. Acad. Sci. USA. 105, 5034-5039.

Link to full publication list >