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The Jaffe laboratory studies protein structure-function relationships using both biochemical and biophysical approaches. We have recently become focused on the roles of protein quaternary structure dynamics in the control of protein function. This follows our discovery that at least one homo-oligomeric protein can dissociate, the dissociated units can change conformation, and these altered conformations support association to a structurally and functionally distinct oligomeric assembly. Unlike the prion phenomenon, our characterized changes in subunit structure are subtle, the oligomeric stoichiometry is finite, and the process is freely reversible. We have associated this structural dynamic with allosteric regulation of protein function, with human disease, and with new opportunities for allosteric drug discovery. The now well established structural dynamic was originally unexpected and we were reticent to accept its validity. However, realizing the novelty of this discovery, we coined the term morpheein to describe proteins that could reversibly dissociate, change conformation, and assemble differently with finite stoichiometry. What we have learned from the prototype morpheein allows us to mine the literature and protein structure databases in search of other proteins that function as morpheeins. We have identified a family of putative morpheeins, many of which can be approached as drug targets, including cancer chemotherapeutic targets.

1. Lawrence SH, Selwood T, Jaffe EK. Diverse clinical compounds alter the quaternary structure and inhibit the activity of an essential enzyme. ChemMedChem. 2011 Apr. 19 [Epub ahead of print].
2. Jaffe EK, Shanmugan D, Gardberg A, Dieterich M, Banumathi S, Stewart LJ, Myler PJ, Roos DS. Crystal structure of Toxoplasma gondii porphobilinogen synthase: Insight on octameric structure and porphobilinogen formation. J Biol Chem. 2011 Mar 7. [Epub ahead of print]. PubMed
3. Shanmugam D, Wu B, Ramirez U, Jaffe EK, Roos DS. Plastid-associated porphobilinogen synthase from Toxoplasma gondii: kinetic and structural properties validate therapeutic potential.� J Biol Chem. 2010 Jul 16;285(29):22122-31. Epub 2010 May 4. PubMed
4. Lawrence SH, Ramirez UD, Selwood T, Stith L, Jaffe EK. Allosteric inhibition of human porphobilinogen synthase. J Biol Chem. 2009 Dec 18;284(51):35807-17. PubMed
5. Lawrence, SH and Jaffe EK. Expanding the Concepts in Protein Structure-Function Relationships and Enzyme Kinetics: Teaching Using Morpheeins. Biochemistry and Molecular Biology Education. 2008;36:274-83.
6. Lawrence SH, Ramirez UD, Tang L, Fazliyez F, Kundrat L, Markham GD, Jaffe EK. Shape shifting leads to small-molecule allosteric drug discovery. Chem Biol. 2008;15:586-96. PubMed
7. Selwood T, Tang L, Lawrence SH, Anokhina Y, Jaffe EK. Kinetics and thermodynamics of the interchange of the morpheein forms of human porphobilinogen synthase. Biochemistry. 2008 47:3245-57.PubMed
8. Jaffe EK, Stith L. ALAD Porphyria Is a Conformational Disease. Am J Hum Genet. 2007 80:329-37.PubMed
9. Tang L, Breinig S, Stith L, Mischel A, Tannir J, Kokona B, Fairman R, Jaffe EK. Single amino acid mutations alter the distribution of human porphobilinogen synthase quaternary structure isoforms (morpheeins). J Biol Chem. 2006 281:6682-90. PubMed
10. Akagi R, Kato N, Inoue R, Anderson KE, Jaffe EK, Sassa S. delta-Aminolevulinate dehydratase (ALAD) porphyria: the first case in North America with two novel ALAD mutations.. Mol Genet Metab. 2006;87:329-36. PubMed
11. Jaffe EK. Morpheeins - a new structural paradigm for allosteric regulation. Trends Biochem Sci. 2005;30:490-7. PubMed
12. Tang L, Stith L, Jaffe EK. Substrate induced interconversion of protein quaternary structure isoforms. J Biol Chem. 2005 280:15786-93. PubMed