Chemically induced proximity in biology and medicine

Science. 2018 Mar 9;359(6380):eaao5902. doi: 10.1126/science.aao5902.

Abstract

Proximity, or the physical closeness of molecules, is a pervasive regulatory mechanism in biology. For example, most posttranslational modifications such as phosphorylation, methylation, and acetylation promote proximity of molecules to play deterministic roles in cellular processes. To understand the role of proximity in biologic mechanisms, chemical inducers of proximity (CIPs) were developed to synthetically model biologically regulated recruitment. Chemically induced proximity allows for precise temporal control of transcription, signaling cascades, chromatin regulation, protein folding, localization, and degradation, as well as a host of other biologic processes. A systematic analysis of CIPs in basic research, coupled with recent technological advances utilizing CRISPR, distinguishes roles of causality from coincidence and allows for mathematical modeling in synthetic biology. Recently, induced proximity has provided new avenues of gene therapy and emerging advances in cancer treatment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Biological Mimicry*
  • CRISPR-Cas Systems
  • Cell- and Tissue-Based Therapy / trends*
  • Chromatin / chemistry
  • Genetic Therapy / trends*
  • Humans
  • Ligands
  • Protein Folding
  • Protein Processing, Post-Translational
  • Proteins / chemistry*
  • Proteolysis
  • Signal Transduction
  • Tacrolimus / analogs & derivatives
  • Tacrolimus / pharmacology
  • Transcription, Genetic

Substances

  • Chromatin
  • FK 1012
  • Ligands
  • Proteins
  • Tacrolimus