Three STEPs Forward: A Trio of Unexpected Structures of PTPN5

Proteins. 2025 Dec;93(12):2112-2127. doi: 10.1002/prot.70013. Epub 2025 Jul 5.

Abstract

Protein tyrosine phosphatases (PTPs) play pivotal roles in myriad cellular processes by counteracting protein tyrosine kinases. Striatal-enriched protein tyrosine phosphatase (STEP, PTPN5) regulates synaptic function and neuronal plasticity in the brain and is a therapeutic target for several neurological disorders. Here, we present three new crystal structures of STEP, each with unexpected features. These include high-resolution conformational heterogeneity at multiple sites, a highly coordinated citrate molecule in the active site, a previously unseen conformational change at an allosteric site, an intramolecular disulfide bond that was characterized biochemically but had never been visualized structurally, and two serendipitous covalent ligand binding events at surface-exposed cysteines that are nearly or entirely unique to STEP among human PTPs. Together, our results offer new views of the conformational landscape of STEP that may inform structure-based design of allosteric small molecules to specifically inhibit this biomedically important enzyme.

Keywords: STEP; X‐ray crystallography; allostery; disulfide; ligand binding; phosphatase.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Amino Acid Sequence
  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Cysteine / chemistry
  • Cysteine / metabolism
  • Disulfides / chemistry
  • Humans
  • Ligands
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Tyrosine Phosphatases, Non-Receptor* / chemistry
  • Protein Tyrosine Phosphatases, Non-Receptor* / metabolism

Substances

  • PTPN5 protein, human
  • Protein Tyrosine Phosphatases, Non-Receptor
  • Cysteine
  • Disulfides
  • Ligands