Computational design of receptor and sensor proteins with novel functions

Loren L. Looger, Mary A. Dwyer, James J. Smith and Homme W. Hellinga ()
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Loren L. Looger: Duke University Medical Center
Mary A. Dwyer: Duke University Medical Center
James J. Smith: Duke University Medical Center
Homme W. Hellinga: Duke University Medical Center

Nature, 2003, vol. 423, issue 6936, 185-190

Abstract: Abstract The formation of complexes between proteins and ligands is fundamental to biological processes at the molecular level. Manipulation of molecular recognition between ligands and proteins is therefore important for basic biological studies1 and has many biotechnological applications, including the construction of enzymes2,3,4, biosensors5,6, genetic circuits7, signal transduction pathways8 and chiral separations9. The systematic manipulation of binding sites remains a major challenge. Computational design offers enormous generality for engineering protein structure and function10. Here we present a structure-based computational method that can drastically redesign protein ligand-binding specificities. This method was used to construct soluble receptors that bind trinitrotoluene, l-lactate or serotonin with high selectivity and affinity. These engineered receptors can function as biosensors for their new ligands; we also incorporated them into synthetic bacterial signal transduction pathways, regulating gene expression in response to extracellular trinitrotoluene or l-lactate. The use of various ligands and proteins shows that a high degree of control over biomolecular recognition has been established computationally. The biological and biosensing activities of the designed receptors illustrate potential applications of computational design.

Date: 2003
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DOI: 10.1038/nature01556

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