Skip to main content
eScholarship
Open Access Publications from the University of California

An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering.

  • Author(s): Keedy, Daniel A
  • Hill, Zachary B
  • Biel, Justin T
  • Kang, Emily
  • Rettenmaier, T Justin
  • Brandão-Neto, José
  • Pearce, Nicholas M
  • von Delft, Frank
  • Wells, James A
  • Fraser, James S
  • et al.

Published Web Location

https://www.ncbi.nlm.nih.gov/pubmed/?term=29877794
No data is associated with this publication.
Abstract

Allostery is an inherent feature of proteins, but it remains challenging to reveal the mechanisms by which allosteric signals propagate. A clearer understanding of this intrinsic circuitry would afford new opportunities to modulate protein function. Here, we have identified allosteric sites in protein tyrosine phosphatase 1B (PTP1B) by combining multiple-temperature X-ray crystallography experiments and structure determination from hundreds of individual small-molecule fragment soaks. New modeling approaches reveal 'hidden' low-occupancy conformational states for protein and ligands. Our results converge on allosteric sites that are conformationally coupled to the active-site WPD loop and are hotspots for fragment binding. Targeting one of these sites with covalently tethered molecules or mutations allosterically inhibits enzyme activity. Overall, this work demonstrates how the ensemble nature of macromolecular structure, revealed here by multitemperature crystallography, can elucidate allosteric mechanisms and open new doors for long-range control of protein function.

Many UC-authored scholarly publications are freely available on this site because of the UC Academic Senate's Open Access Policy. Let us know how this access is important for you.

Item not freely available? Link broken?
Report a problem accessing this item