An expanded trove of fragment-bound structures for the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data

Structure. 2024 Aug 8;32(8):1231-1238.e4. doi: 10.1016/j.str.2024.05.010. Epub 2024 Jun 10.

Abstract

Due to their low binding affinities, detecting small-molecule fragments bound to protein structures from crystallographic datasets has been a challenge. Here, we report a trove of 65 new fragment hits for PTP1B, an "undruggable" therapeutic target enzyme for diabetes and cancer. These structures were obtained from computational analysis of data from a large crystallographic screen, demonstrating the power of this approach to elucidate many (∼50% more) "hidden" ligand-bound states of proteins. Our new structures include a fragment hit found in a novel binding site in PTP1B with a unique location relative to the active site, one that links adjacent allosteric sites, and, perhaps most strikingly, a fragment that induces long-range allosteric protein conformational responses. Altogether, our research highlights the utility of computational analysis of crystallographic data, makes publicly available dozens of new ligand-bound structures of a high-value drug target, and identifies novel aspects of ligandability and allostery in PTP1B.

Keywords: PTP1B; X-ray crystallography; allosteric ligands; allostery; computational crystallography; fragment screening; phosphatases; protein structure.

MeSH terms

  • Allosteric Regulation
  • Allosteric Site*
  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Ligands
  • Models, Molecular
  • Protein Binding*
  • Protein Conformation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1* / chemistry
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1* / metabolism
  • Small Molecule Libraries / chemistry

Substances

  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • PTPN1 protein, human
  • Ligands
  • Enzyme Inhibitors
  • Small Molecule Libraries