On the most basic level, protein engineering entails changing an existing protein sequence for a new purpose.1 Although a rather young field, the last decade has seen a giant leap in the understanding of protein structure and function. The advent of DNA shuffling in 1994, for example, has led to increased activity, thermodynamic stability, and folding in certain enzymes.2 Despite great advances in improving the activities of certain proteins, engineering proteins with new biomolecular functions has largely remained beyond scientists' capabilities.Two approaches towards protein engineering have been applied, consisting of both rational and evolutionary engineering designs.3 The former generally necessitates an extensive knowledge of the protein's structure, active site, mechanism and co-factors in order to reach a desired goal. These techniques have predictably had much difficulty in creating proteins with new functions. Evolutionary approaches, however, seem to be the future of protein engineering. These methods consist of using nature's principle of creating diversity through mutations and then designing selection methods to find proteins with a desired function.
[...] 869- Ostermeier, M. Molecular Switches. Retrieved May from http://www.jhu.edu/~cheme/ostermeier/MOresearch.html Ostermeier, M. Applied Molecular Evolution Abstract. Retrieved May from http://www.jhu.edu/~biophys/introbiomed/ab- Ostermeier.pdf Ostermeier, M. Lecture. March Sneiderman Sneiderman Ostermeier, M. Lecture. March Ostermeier, M. et al. (1999) A combinatorial approach to hybrid enzymes independent of DNA homology. Nat Biotechnol [...]
[...] If successful, however, it could have widespread implications for not only antibiotic delivery but for any directed drug delivery system to an “infected” cell, whether it is bacterial, viral or cancerous. Ostermeier's molecular switch technology is a monumental achievement because it allows scientists to use pre-existing proteins for new bio-molecular functions. The successful creation of molecular switches, phenomena widely used by nature, serves as a vital stepping-stone in the progress of protein engineering and has placed Ostermeier at the forefront of the field's leading researchers. [...]
[...] (1999) A combinatorial approach to hybrid enzymes independent of DNA homology. Nat Biotechnol 17: 1205- Steipe, 60- Ostermeier, M. Lecture. March Steipe, 68- Ostermeier, M. (2002) Theoretical distribution of truncation lengths in incremental truncation libraries. Biotechnol. Bioeng 564- Steipe Ostermeier, M. Applied Molecular Evolution Abstract. Retrieved May from http://www.jhu.edu/~biophys/introbiomed/ab- Ostermeier.pdf Sneiderman, Phil. Protein engineering produces a Molecular ‘Switch' The Johns Hopkins Gazette 1-3.Retrieved May from http://www.jhu.edu/~gazette/2003/31mar03/31switch.html Lodish, H., Berk, A., Zipursky, S.L., Matsudaira, P Molecular Cell Biology. 4th ed. New York: W.H. [...]
[...] Ostermeier's research is centered on creating molecular switches through combining two proteins (protein A and protein so that protein A regulates the function protein B. This allosteric regulation could be controlled by a diverse array of signals such as pH, ligand binding, and protein-protein interactions.8 Using a technique called domain insertion, he has successfully linked two proteins, beta-lactamase and a maltose bind protein, so that the presence of maltose enhances the function of beta-lactamase. Discussion of Domain Insertion Technique in creating Molecular Switches The presence of a molecular switch is quite common in many natural proteins such as the G protein found in the GPCR signaling pathway. [...]
[...] Finally, this integrin receptor tightly binds to an Ig-CAM of the infected endothelial cell causing the leukocyte to move between two endothelial cells into the underlying infected tissue.22 Creating a protein that would release an antibiotic specifically after an “extravasation” process would obviously be more complicated than the beta- lactamase / maltose example previously discussed because two molecular switches would be required: After binding the Ig-CAM at the infected tissue site, a binding site is exposed for another diseased cell-signal such as a cytokine and upon cytokine binding, the antibiotic is released into the infected tissue. [...]
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