Computational design of a modular protein sense-response system
Category
Published on
Type
journal-article
Author
Anum A. Glasgow and Yao-Ming Huang and Daniel J. Mandell and Michael Thompson and Ryan Ritterson and Amanda L. Loshbaugh and Jenna Pellegrino and Cody Krivacic and Roland A. Pache and Kyle A. Barlow and Noah Ollikainen and Deborah Jeon and Mark J. S. Kelly and James S. Fraser and Tanja Kortemme
Citation
Glasgow, A.A. et al., 2019. Computational design of a modular protein sense-response system. Science, 366(6468), pp.1024–1028. Available at: http://dx.doi.org/10.1126/science.aax8780.
Abstract
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.
