Advanced Methods for Accessing Protein Shape-Shifting Present New Therapeutic Opportunities

Trends Biochem Sci. 2019 Apr;44(4):351-364. doi: 10.1016/j.tibs.2018.11.007. Epub 2018 Dec 14.


A protein is a dynamic shape-shifter whose function is determined by the set of structures it adopts. Unfortunately, atomically detailed structures are only available for a few conformations of any given protein, and these structures have limited explanatory and predictive power. Here, we provide a brief historical perspective on protein dynamics and introduce recent advances in computational and experimental methods that are providing unprecedented access to protein shape-shifting. Next, we focus on how these tools are revealing the mechanism of allosteric communication and features like cryptic pockets; both of which present new therapeutic opportunities. A major theme is the importance of considering the relative probabilities of different structures and the control one can exert over protein function by modulating this balance.

Keywords: allostery; cryptic pockets; protein dynamics.

Publication types

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

MeSH terms

  • Computational Biology*
  • Humans
  • Protein Conformation
  • Proteins / chemistry*
  • Proteins / metabolism


  • Proteins