Designing Small-Molecule Switches for Protein-Protein Interactions

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Science  16 Jun 2000:
Vol. 288, Issue 5473, pp. 2042-2045
DOI: 10.1126/science.288.5473.2042

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Mutations introduced into human growth hormone (hGH) (Thr175 → Gly–hGH) and the extracellular domain of the hGH receptor (Trp104 → Gly–hGHbp) created a cavity at the protein-protein interface that resulted in binding affinity being reduced by a factor of 106. A small library of indole analogs was screened for small molecules that bind the cavity created by the mutations and restore binding affinity. The ligand 5-chloro-2-trichloromethylimidazole was found to increase the affinity of the mutant hormone for its receptor more than 1000-fold. Cell proliferation and JAK2 phosphorylation assays showed that the mutant hGH activates growth hormone signaling in the presence of added ligand. This approach may allow other protein-protein and protein–nucleic acid interactions to be switched on or off by the addition or depletion of exogenous small molecules.

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