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STEP (PTPN5) with active-site disulfide bond and allosteric-site loop shift
Structural highlights
FunctionPTN5_HUMAN May regulate the activity of several effector molecules involved in synaptic plasticity and neuronal cell survival, including MAPKs, Src family kinases and NMDA receptors.[1] Publication Abstract from PubMedProtein 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. Three STEPs forward: A trio of unexpected structures of PTPN5.,Guerrero L, Ebrahim A, Riley BT, Kim SH, Bishop AC, Wu J, Han YN, Tautz L, Keedy DA bioRxiv [Preprint]. 2024 Nov 21:2024.11.20.624168. doi: , 10.1101/2024.11.20.624168. PMID:39605455[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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