Shohei Koide

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 using designer proteins. We are now able to generate binding proteins that recognize a target of interest tightly and exquisitely selectively. We utilize them as custom-made, selective inhibitors of protein-protein interactions to dissect signaling networks and to control aberrant proteins responsible for human diseases. We currently focus on signaling mediated by tyrosine phosphorylation and histone modification. Importantly, our approach does not require modification of the endogenous genome of the cells and it closely mimics how drugs influence their targets, making it also a powerful approach for drug target discovery.

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...

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

Biancalana M, Makabe K & Koide S (2010) Minimalist design of water-soluble cross-β architecture. Proc Natl Acad Sci U S A, 107, 3469-74.   Link

Huang J, Koide A, Makabe K & Koide S (2008) Design of protein function leaps by directed domain interface evolution. Proc Natl Acad Sci U S A, 105, 6578-6583.  Link

Gilbreth RN, Esaki K, Koide A, Sidhu SS & Koide S. (2008). A dominant conformational role for amino acid diversity in minimalist protein-protein interfaces. J Mol Biol, 381, 407-418.  Link

Biancalana M, Makabe K, Koide A & Koide S. (2009) Molecular mechanism of thioflavin-T binding to the surface of β-rich peptide self-assemblies. J Mol Biol, 385, 1052-1063. (top cited JMB article 2009-2011)  Link

Koide S. (2009) Design and engineering of synthetic recognition interfaces using non-antibody scaffolds. in Protein Engineering and Design (Ed. Cochran J & Park S). Taylor & Francis. 

Koide S (2009) Generation of novel protein functions by domain combinations and rearrangements. Curr Opin Biotechnol, 20, 398-404. 

Koide A., Gilbreth R, Esaki K, Tereshko V. & Koide S. (2007) High-affinity single-domain binding proteins with a binary code interface, Proc Natl Acad Sci U S A, 104,6632-6637.  Link

Fellouse FA, Esaki K, Birtalan S, Raptis D, Cancasci VJ, Koide A, Jhurani P, Vasser M, Wiesmann C, Kossiakoff AA, Koide S & Sidhu SS (2007) High-throughput generation of synthetic antibodies from highly functional minimalist phage-displayed libraries, J Mol Biol 373, 924–940.  Link

Koide, A., Bailey, C. W., Huang, X. and Koide, S. (1998). "The fibronectin type III domain as a scaffold for novel binding proteins." J. Mol. Biol. 284: 1141-1151.   Link

Koide, S., Huang, X., Link, K., Koide, A., Bu, Z. and Engelman, D. M. (2000). "Design of single-layer beta-sheets without a hydrophobic core." Nature 403: 456-460.   Link

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