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PreprintCited by 2Protein Tyrosine PhosphatasesEnzyme Structure and FunctionProtein Structure and Dynamics

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Three STEPs forward: A trio of unexpected structures of PTPN5

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Guerrero, Liliana, Ebrahim, Ali, Riley, Blake T., Kim, Sean H., Bishop, Anthony C., Wu, Jiaqian, Han, Ye Na, Tautz, Lutz, Keedy, Daniel A.·2024·Proteins Structure Function and Bioinformatics
DOI 10.1101/2024.11.20.624168PMC PMC12270549

Preprint — published as 10.1002/prot.70013

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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, and 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.

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Metadata

Authors
Guerrero, L., Ebrahim, A., Riley, B. T., Kim, S. H., Bishop, A. C., Wu, J., Han, Y. N., Tautz, L., & Keedy, D. A.
Affiliations
  • The Graduate Center, CUNY (US)
  • CUNY Advanced Science Research Center (US)
  • Amherst College (US)
  • Sanford Burnham Prebys Medical Discovery Institute (US)
Corresponding author
Keedy, Daniel A.
ORCID
Venue
Proteins Structure Function and Bioinformatics
Publisher
openRxiv
Published
2024-11-21
Volume
93
Issue
12
Pages
2112-2127
ISSN
0887-3585 (ISSN-L)
DOI
10.1101/2024.11.20.624168
PMC
PMC12270549
OpenAlex
W4412047367
Cited by
2
References
1
Citations by year
2025: 2
FWCI
0.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Proteins Structure Function and Bioinformatics (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • SSRN Electronic Journal (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • National Science Foundation
  • U.S. Department of Energy
  • Empire State Development Corporation
  • National Institute on Aging (R21AG067155, RF1AG087011, R01AG065387)
  • National Cancer Institute (P30CA030199)
  • National Institute of General Medical Sciences (P41GM111244, R15GM071388, T32GM136499, R35GM133769, P30GM124166)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
PTPN5, striatal-enriched protein tyrosine phosphatase, protein tyrosine phosphatase, crystal structure, conformational heterogeneity, allosteric site, intramolecular disulfide bond, cysteine residues, allosteric inhibitors, structure-based drug design, synaptic function

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