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

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

SUBMITTER: Keedy DA 

PROVIDER: S-EPMC6039181 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature