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Developmental Therapeutics 

Lynne J Regan PhD

Professor of Molecular Biophysics and Biochemistry and of Chemistry

Research Interests

Mental retardation; Protein-protein interactions; Fragile X Mental Retardation Protein (FMRP); Protein-based nanomaterials


Research Summary

  1. Protein Structure, Function, and Design: We are interested in the fundamental question: How does a protein's primary sequence specify its three dimensional structure? In addition, we are investigating the mechanisms by which proteins achieve the exquisite specificity and efficiency that are characteristic of protein-ligand interactions and enzymatic catalysis. Our research focuses upon small proteins, particularly four-helix bundle proteins, that are amenable to study by a variety of biophysical, biochemical and molecular biological techniques.
  2. Designed Metal-Binding Proteins: We have introduced novel metal-binding sites into two proteins: a designed four-helix bundle protein, a4 and the B1 domain of IgG-binding protein G. The metal-site designs are for both structural and catalytic tetrahedral Zn(II) sites. The structural sites enhance the stability of the proteins, whereas the catalytic sites aim to exploit the powerful nucleophilic activity of Zn(II)- bound water and to mimic natural enzymes such as carbonic anhydrase and carboxypeptidase.
  3. A Model System to Study b-Sheet Formation: The factors that are important for a-helix formation are much better understood than those for b-sheet formation. This is largely because tractable model systems in which to study b-sheet formation have been lacking. We are using the B1 domain of Ig-binding protein G as an ideal model system in which to study b-sheet formation. We have determined both the intrinsic b-sheet forming propensities of the amino acids and the energetics of pair-wise interactions across two strands of a b-sheet. The results of these studies allow us to formulate the first guidelines for rational b-sheet design.

Extensive Research Description

Research interests of the Regan lab encompass protein structure, folding and design; protein-protein interactions and protein-RNA interactions. Our research is problem based, and we use whatever techniques are most appropriate as a particular project develops. Our research ranges from fundamental studies of protein stability to the design of novel protein-based nano-materials. Our interest in protein-protein interactions ranges from the design of proteins with novel binding activities and characterization of their properties using a range of techniques including fluorescence, circular dichroism, surface plasmon resonance, NMR and x-ray crystallography to the specific inhibition of protein-protein interactions in vivo as a route to a novel class of anti-breast cancer agents. Our interest in protein-RNA interactions is focused on structure and function of Fragile X Mental Retardation Protein (FMRP). Fragile X Mental Retardation Syndrome is the most common cause of inherited mental retardation in humans, and is caused by lack of functional FMRP. Here our approaches range from structural studies of FMRP, to whole animal profiling of RNA and protein expression patterns in wild-type versus FMRP knock-out animals.


Selected Publications

  • Champion EA, Kundrat L, Regan L, Baserga SJ. Protein Eng Des Sel. 2009 Jul;22(7):431-9. Epub 2009 Jun 10.
  • Jackrel ME, Valverde R, Regan L. Protein Sci. 2009 Apr;18(4):762-74. PMID: 19309728 [PubMed - indexed for MEDLINE]
  • Yi F, Zhu P, Southall N, Inglese J, Austin CP, Zheng W, Regan L. J Biomol Screen. 2009 Mar;14(3):273-81. Epub 2009 Feb 11.
  • Yi F, Regan L. ACS Chem Biol. 2008 Oct 17;3(10):645-54. Epub 2008 Sep 12.

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