Computational design of a modular protein sense-response system

Science. 2019 Nov 22;366(6468):1024-1028. doi: 10.1126/science.aax8780.


Sensing and responding to signals is a fundamental ability of living systems, but despite substantial progress in the computational design of new protein structures, there is no general approach for engineering arbitrary new protein sensors. Here, we describe a generalizable computational strategy for designing sensor-actuator proteins by building binding sites de novo into heterodimeric protein-protein interfaces and coupling ligand sensing to modular actuation through split reporters. Using this approach, we designed protein sensors that respond to farnesyl pyrophosphate, a metabolic intermediate in the production of valuable compounds. The sensors are functional in vitro and in cells, and the crystal structure of the engineered binding site closely matches the design model. Our computational design strategy opens broad avenues to link biological outputs to new signals.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Ankyrin Repeat
  • Binding Sites
  • Biosensing Techniques
  • Computational Biology
  • Computer Simulation
  • Crystallography, X-Ray
  • Ligands
  • Maltose-Binding Proteins / chemistry
  • Maltose-Binding Proteins / metabolism
  • Models, Molecular
  • Polyisoprenyl Phosphates / metabolism*
  • Protein Engineering*
  • Protein Multimerization*
  • Proteins / chemistry*
  • Proteins / genetics
  • Proteins / metabolism
  • Sesquiterpenes / metabolism*


  • Ligands
  • Maltose-Binding Proteins
  • Polyisoprenyl Phosphates
  • Proteins
  • Sesquiterpenes
  • farnesyl pyrophosphate