Research Summary / Selected Publications
We are interested in creating proteins with novel functions and using such designer proteins to control biology. Our research is interdisciplinary, integrating approaches in directed evolution, structural biology, protein chemistry, spectroscopy and cell biology.
Protein Design. We have taken a "minimalist" approach for understanding the determinants for tight and specific interfaces (e.g. how much chemical and structural diversity is required for affinity and specificity?) by constructing small but highly functional binding proteins. This exercise has substantially advanced our understanding of the molecular mechanisms underlying molecular recognition and protein evolution.
We use two platforms. The first is the "monobodies", a small protein that presents surface binding loops, and "synthetic antibodies", both representing a ubiquitous mode of binding seen in natural proteins. The second is the "affinity clamps", a two-domain architecture that we have created specifically for recognizing flexible peptide segments. We combine structure-guided design and directed evolution to efficiently generate synthetic binding proteins.
Controlling signaling and epigenetic networks...
Gibreth RN, Koide S. (2012) Structural Insights for Engineering Binding Proteins Based on Non-Antibody Scaffolds. Curr Opin Struct Biol, 22:413-20. PubMed
Koide A, Wojcik J, Gilbreth RN, Hoey RJ, Koide S. (2012) Teaching an Old Scaffold New Tricks: Monobodies Constructed Using Alternative Surfaces of the FN3 Scaffold. J Mol Biol. 415:393-405. PubMed
Grebien F, Hantschel O, Wojcik J, Kaupe I, Kovacic B, Wyrzucki AM, Gish GD, Cerny-Reiterer S, Koide A, Beug H, Pawson T, Valent P, Koide S, Superti-Furga G. (2011) Targeting the SH2-Kinase Interface in Bcr-Abl Inhibits Leukemogenesis. Cell 147:306-19. PubMed
Gilbreth RN, Truong K, Madu I, Koide A, Wojcik JB, Li NS, Piccirilli JA, Chen Y, Koide S (2011) Isoform-specific monobody inhibitors of small ubiquitin-related modifiers engineered using structure-guided library design. Proc Natl Acad Sci U S A. 108:7751-6. PubMed
Wojcik J, Hantschel O, Grebien F, Kaupe I, Bennett KL, Barkinge J, Jones RB, Koide A, Superti-Furga G & Koide S. (2010) A potent and highly specific inhibitor of c-Abl1 SH2 domain. Nature Struct Mol Biol 17, 519-527 Link