An evolution-based strategy for engineering allosteric regulation

David Pincus, Orna Resnekov, Kimberly A. Reynolds

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Allosteric regulation provides a way to control protein activity at the time scale of milliseconds to seconds inside the cell. An ability to engineer synthetic allosteric systems would be of practical utility for the development of novel biosensors, creation of synthetic cell signaling pathways, and design of small molecule pharmaceuticals with regulatory impact. To this end, we outline a general approach - termed rational engineering of allostery at conserved hotspots (REACH) - to introduce novel regulation into a protein of interest by exploiting latent allostery that has been hard-wired by evolution into its structure. REACH entails the use of statistical coupling analysis (SCA) to identify 'allosteric hotspots' on protein surfaces, the development and implementation of experimental assays to test hotspots for functionality, and a toolkit of allosteric modulators to impinge on endogenous cellular circuitry. REACH can be broadly applied to rewire cellular processes to respond to novel inputs.

Original languageEnglish (US)
Article number025002
JournalPhysical Biology
Volume14
Issue number2
DOIs
Publication statusPublished - Apr 28 2017

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Keywords

  • engineering allosteric regulation
  • REACH
  • Sectors

ASJC Scopus subject areas

  • Structural Biology
  • Biophysics
  • Molecular Biology
  • Cell Biology

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