Please tell me about your favorite protein structure papers, or suggest additions to this list: emartz@microbio.umass.edu.
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bacteria |
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Five members of the E. coli periplasmic binding protein superfamily that bound monosaccharides or amino acids were redesigned to bind TNT, L-lactate, or serotonin. These target ligands are neutral, anionic, and cationic respectively. Only L-lactate is chiral. Successes with all three and multiple original specifities exclude the results being merely a lucky fluke. Ligand-contacting residues were mutated computationally, while the ligand underwent translation and rotation restricted to a volume roughly occupied by the natural ligand. The combinatorial problem (1053 - 1076 cases) was solved with a novel algorithm based upon dead-end elimination theorems. Each redesign took about three days on a 20-processor computer cluster.
In a further tour de force, redesigned sugar chemotaxis receptors were shown to enable E. coli to respond to TNT and L-lactate (using a re-engineered signal transduction pathway that increased b-galactosidase gene expression). Potential biosensor applications include locating the sources of underwater TNT plumes leaching from unexploded military ordnance, or locating landmines. Biosensors for L-lactate or serotonin have potential clinical applications. Chirally selective receptors could aid the "preparation of optically pure pharmaceuticals from racemic mixtures".
Finally, the methods may be extended to design of enzymes, with the advantage that the virtual transition-state intermediate may more accurately reflect the true transition state than the chemically stable transition state analogs heretofore used to select catalytic antibodies.
Crystallography |
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