Computational redesign of protein-protein interaction specificity

Tanja Kortemme, Lukasz A. Joachimiak, Alex N. Bullock, Aaron D. Schuler, Barry L. Stoddard, David Baker

Research output: Contribution to journalArticlepeer-review

262 Scopus citations


We developed a 'computational second-site suppressor' strategy to redesign specificity at a protein-protein interface and applied it to create new specifically interacting DNase-inhibitor protein pairs. We demonstrate that the designed switch in specificity holds in in vitro binding and functional assays. We also show that the designed interfaces are specific in the natural functional context in living cells, and present the first high-resolution X-ray crystallographic analysis of a computer-redesigned functional protein-protein interface with altered specificity. The approach should be applicable to the design of interacting protein pairs with novel specificities for delineating and re-engineering protein interaction networks in living cells.

Original languageEnglish (US)
Pages (from-to)371-379
Number of pages9
JournalNature Structural and Molecular Biology
Issue number4
StatePublished - Apr 2004
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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