9EEY

STEP (PTPN5) with active-site disulfide bond and allosteric-site loop shift

Summary for 9EEY

• Entry DOI: 10.2210/pdb9eey/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 5, SULFATE ION (3 entities in total)
• Functional Keywords: step, ptpn5, allostery, disulfide, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35396.97

Authors

Guerrero, L.,Ebrahim, A.,Riley, B.T.,Keedy, D.A. (deposition date: 2024-11-19, release date: 2024-12-11)

Primary citation

Guerrero, L.,Ebrahim, A.,Riley, B.T.,Kim, S.H.,Bishop, A.C.,Wu, J.,Han, Y.N.,Tautz, L.,Keedy, D.A.
Three STEPs forward: A trio of unexpected structures of PTPN5.
Biorxiv, 2024

PubMed 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 that inhibits enzyme activity, 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.

PubMed: 39605455
DOI: 10.1101/2024.11.20.624168

Experimental method

X-RAY DIFFRACTION (1.75 Å)