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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. Selwood T, Jaffe EK. Dynamic dissociating homo-oligomers and the control of protein function. Arch Biochem Biophys. 2012 Mar 15;519(2):131-43. PubMed
2. Jaffe EK, Lawrence SH. Allostery and the dynamic multimerization of porphobilinogen synthase. Arch Biochem Biophys. 2012;519:144-53. PubMed
3. Lawrence SH, Selwood T, Jaffe EK. Diverse clinical compounds alter the quaternary structure and inhibit the activity of an essential enzyme. ChemMedChem. 2011 Jun 6;6(6):1067-73. doi: 10.1002/cmdc.201100009. PubMed
4. 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. PubMed
5. Jaffe EK. Morpheeins, a new pathway for allosteric drug discovery. Open Conf Proc J. 2010;1:1-6. PubMed
6. 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. PubMed
7. 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
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. Jaffe EK. Morpheeins - a new structural paradigm for allosteric regulation. Trends Biochem Sci. 2005;30:490-7. PubMed