The goals of our research are to elucidate factors governing molecular recognition events underlying protein function and to produce novel function by exploiting such knowledge. Current research topics include:
(i) Minimalist interaction interfaces. Protein-protein interactions are central to biological regulation. Natural protein interaction interfaces are large and complex. We aim to define the "minimalist" requirements for tight and specific interfaces (e.g. how large does an interface needs to be?; how much chemical and structural diversity is required for affinity and specificity?). Our research focuses on interactions mediated by surface loops, ubiquitously seen in antibodies and cytokine receptors. We employ iterative processes of engineering synthetic binding proteins by altering loops of a small protein and analyzing the structure and function of binding proteins. Our research has helped establish the concept of "molecular scaffolds" and the field of "antibody mimics."
(ii) Peptide self-assembly. Self-assembly of peptides into water-insoluble, beta-sheet-rich fibrils is implicated in protein misfolding diseases (e.g. Alzheimer's) and it is also a process leading to novel nanomaterials. We aim to understand contributions of various factors governing peptide self-assembly and design novel nanostructures. We have developed a unique model system called "peptide self-assembly mimic", which captures the essence of peptide self-assembly within a water-soluble protein and enables us to investigate atomic structures and energetics of otherwise recalcitrant materials.
(iii) Structural biology. We use solution NMR spectroscopy, x-ray crystallography and the antibody mimic technology to characterize the atomic structure and dynamics of proteins involved in signal transduction. As a member of the Structural Genomics Initiative, we are developing powerful technologies to facilitate protein structure determination.
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. Link
Dutta S, Koide A & Koide S. (2008) High-throughput analysis of the protein sequence-stability landscape using a quantitative "yeast surface two-hybrid" system and fragment reconstitution. J Mol Biol, 382, 721-733. Link
Ye J, Fellouse FA, Koide A, Sidhu SS, Koide S, Kossiakoff AA & Piccirilli JA (2008) Synthetic antibodies for specific recognition and crystallization of structured RNA. Proc Natl Acad Sci U S A, 105, 82-87. Link
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
Sidhu SS & Koide S. (2007). Phage display for engineering and analyzing molecular recognition interfaces. Curr Opin Struct Biol, 17, 481-487. 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, Tereshko V, Uysal S, Margalef K, Kossiakoff AA & Koide S (2007) Exploring the capacity of minimalist protein interfaces: interface energetics and affinity maturation to picomolar KD of a single-domain antibody with a flat paratope, J Mol Biol 373, 941–953. Link
Makabe K, McElheny D, Tereshko V, Hilyard V, Gawlak G, Yan S, Koide A & Koide S. (2006) Atomic structures of peptide self-assembly mimics. Proc Natl Acad Sci USA, 103, 17753-8. 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.
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Koide, A., Abbatiello, S., Rothgery, L. & Koide, S., (2002) Probing protein conformational changes in living cells using designer binding proteins: application to the estrogen receptor, Proc. Natl. Acad. Sci. USA 99: 1253-1258. 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.
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Yan, S., Kennedy, S.D. & Koide, S. (2002) Thermodynamic and Kinetic Exploration of the Energy Landscape of Borrelia OspA by Native State Hydrogen Exchange, J. Mol. Biol. 323: 363-375. 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. Link
Dutta S, Koide A & Koide S. (2008) High-throughput analysis of the protein sequence-stability landscape using a quantitative "yeast surface two-hybrid" system and fragment reconstitution. J Mol Biol, 382, 721-733. Link
Ye J, Fellouse FA, Koide A, Sidhu SS, Koide S, Kossiakoff AA & Piccirilli JA (2008) Synthetic antibodies for specific recognition and crystallization of structured RNA. Proc Natl Acad Sci U S A, 105, 82-87. Link
