ArticleBiochemistry2015
Targeting a cryptic allosteric site for selective inhibition of the oncogenic protein tyrosine phosphatase Shp2.
Article in Biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
28 citing papers in PubMed, 63 citations in OpenAlex.
- Mapping the SHP2 Allosteric Pocket With Target-Biased Covalent Fragments.Chembiochem : a European journal of chemical biology · 2026Article
- Article
- Opening and closing of a cryptic pocket in VP35 toggles it between two different RNA-binding modes.eLife · 2025Article
- Covalent-Allosteric Inhibitors: Do We Get the Best of Both Worlds?Journal of medicinal chemistry · 2025Review
- Recent computational advances in the identification of cryptic binding sites for drug discovery.Bioinformatics advances · 2025Review
- Single Ion Pair Is Essential for Stabilizing SHP2's Open Conformation.Biochemistry · 2024Article
- Targeting Nonconserved and Pathogenic Cysteines of Protein Tyrosine Phosphatases with Small Molecules.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Destabilization of the SHP2 and SHP1 protein tyrosine phosphatase domains by a non-conserved "backdoor" cysteine.Biochemistry and biophysics reports · 2022Article
- Inhibition of SHP2 and SHP1 Protein Tyrosine Phosphatase Activity by Chemically Induced Dimerization.ACS omega · 2022Article
- Protein tyrosine phosphatases in cell adhesion.The Biochemical journal · 2021Review
- Targeting a Pathogenic Cysteine Mutation: Discovery of a Specific Inhibitor of Y279C SHP2.Biochemistry · 2020Article
- Targeting the C-Terminal Domain Small Phosphatase 1.Life (Basel, Switzerland) · 2020Review
- Beyond the Cell Surface: Targeting Intracellular Negative Regulators to Enhance T cell Anti-Tumor Activity.International journal of molecular sciences · 2019Review
- Chemical activation of divergent protein tyrosine phosphatase domains with cyanine-based biarsenicals.Scientific reports · 2019Article
- PTPσ inhibitors promote hematopoietic stem cell regeneration.Nature communications · 2019Article
- Small Molecule Inhibitor that Stabilizes the Autoinhibited Conformation of the Oncogenic Tyrosine Phosphatase SHP2.Journal of medicinal chemistry · 2019Article
- SHP-2 in Lymphocytes' Cytokine and Inhibitory Receptor Signaling.Frontiers in immunology · 2019Review
- The Allosteric Site on SHP2's Protein Tyrosine Phosphatase Domain is Targetable with Druglike Small Molecules.ACS omega · 2018Article
- Cryptic binding sites on proteins: definition, detection, and druggability.Current opinion in chemical biology · 2018Review
- Optimized allosteric inhibition of engineered protein tyrosine phosphatases with an expanded palette of biarsenical small molecules.Bioorganic & medicinal chemistry · 2018Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Protein tyrosine phosphatases (PTPs) have been the subject of considerable pharmaceutical-design efforts because of the ubiquitous connections between misregulation of PTP activity and human disease. PTP-inhibitor discovery has been hampered, however, by the difficulty in identifying cell-permeable compounds that can selectively target PTP active sites, and no PTP inhibitors have progressed to the clinic. The identification of allosteric sites on target PTPs therefore represents a potentially attractive solution to the druggability problem of PTPs. Here we report that the oncogenic PTP Shp2 contains an allosteric-inhibition site that renders the enzyme sensitive to potent and selective inhibition by cell-permeable biarsenical compounds. Because Shp2 contains no canonical tetracysteine biarsenical-binding motif, the enzyme's inhibitor-binding site is not readily predictable from its primary or three-dimensional structure. Intriguingly, however, Shp2's PTP domain does contain a cysteine residue (C333) at a position that is removed from the active site and is occupied by proline in other classical PTPs. We show that Shp2's unusual cysteine residue constitutes part of a Shp2-specific allosteric-inhibition site, and that Shp2's sensitivity to biarsenicals is dependent on the presence of the naturally occurring C333. The determinative role of this residue in conferring inhibitor sensitivity is surprising because C333's side chain is inaccessible to solvent in Shp2 crystal structures. The discovery of this cryptic Shp2 allosteric site may provide a means for targeting Shp2 activity with high specificity and suggests that buried-yet-targetable allosteric sites could be similarly uncovered in other protein families.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.