ArticleJournal of the American Chemical Society2019
Uncovering the Molecular Interactions in the Catalytic Loop That Modulate the Conformational Dynamics in Protein Tyrosine Phosphatase 1B.
Article in Journal of the American Chemical Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed.
- NMR relaxation dispersion reveals an order of magnitude range of acid loop motions in protein tyrosine phosphatase 1B.Journal of magnetic resonance (San Diego, Calif. : 1997) · 2026Article
- Cancer-Causing Mutations Alter the Interplay Between Loop Dynamics and Catalysis in the Protein Tyrosine Phosphatases SHP-1 and SHP-2.bioRxiv : the preprint server for biology · 2026Article
- Conformational Dynamics and Catalytic Backups in a Hyper-thermostable Engineered Archaeal Protein Tyrosine Phosphatase.JACS Au · 2026Article
- Loop dynamics, allostery, and function in protein tyrosine phosphatases: insights from molecular simulations.Biochemical Society transactions · 2026Review
- WatCon: A Python Tool for Analysis of Conserved Water Networks Across Protein Families.JACS Au · 2025Article
- Distal Mutations Rewire Allosteric Networks to Control Substrate Specificity in PTP1B.Biochemistry · 2025Article
- Approaches for regulating enzyme activities: Recent advances in experiment and computation.Current opinion in structural biology · 2025Review
- Hepatic ASPG-mediated lysophosphatidylinositol catabolism impairs insulin signal transduction.The EMBO journal · 2025Article
- Deep mutational scanning of the multi-domain phosphatase SHP2 reveals mechanisms of regulation and pathogenicity.Nature communications · 2025Article
- The Fascinating Intricacy of pSer/Thr-Specific Phosphatases and Their Higher-Order Complexes: Emerging Concepts.Biochemistry · 2025Review
- Motif-VI loop acts as a nucleotide valve in the West Nile Virus NS3 Helicase.Nucleic acids research · 2024Article
- Allostery in Protein Tyrosine Phosphatases is Enabled by Divergent Dynamics.Journal of chemical information and modeling · 2024Article
- MultiscaleJournal of chemical information and modeling · 2024Article
- Protein Tyrosine Phosphatase regulation by Reactive Oxygen Species.Advances in cancer research · 2024Review
- Sequence - dynamics - function relationships in protein tyrosine phosphatases.QRB discovery · 2024Article
- Interaction of Vanadium Complexes with Proteins: Revisiting the Reported Structures in the Protein Data Bank (PDB) since 2015.Molecules (Basel, Switzerland) · 2023Review
- Analysis of neutral mutational drift in an allosteric enzyme.Protein science : a publication of the Protein Society · 2023Article
- Loop dynamics and the evolution of enzyme activity.Nature reviews. Chemistry · 2023Review
- A Conserved Local Structural Motif Controls the Kinetics of PTP1B Catalysis.Journal of chemical information and modeling · 2023Article
- Deconstructing allostery by computational assessment of the binding determinants of allosteric PTP1B modulators.Communications chemistry · 2023Article
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4 authors.
Funding
Abstract
Active-site loops are integral to the function of numerous enzymes. They enable substrate and product binding and release, sequester reaction intermediates, and recruit catalytic groups. Here, we examine the catalytic loop in the enzyme protein tyrosine phosphatase 1B (PTP1B). PTP1B has a mobile so-called WPD loop (named for its three N-terminal residues) that initiates the dephosphorylation of phosphor-tyrosine substrates upon loop closure. We have combined X-ray crystallography, solution NMR, and pre-steady-state kinetics experiments on wild-type and five WPD loop mutants to identify the relationships between the loop structure, dynamics, and function. The motions of the WPD loop are modulated by the formation of weak molecular interactions, where perturbations of these interactions modulate the conformational equilibrium landscape. The point mutants in the WPD loop alter the loop equilibrium position from a predominantly open state (P185A) to 50:50 (F182A), 35:65 (P188A), and predominantly closed states (T177A and P188A). Surprisingly, there is no correlation between the observed catalytic rates in the loop mutants and changes to the WPD loop equilibrium position. Rather, we observe a strong correlation between the rate of dephosphorylation of the phosphocysteine enzyme intermediate and uniform millisecond motions, not only within the loop but also in the adjacent α-helical domain of PTP1B. Thus, the control of loop motion and thereby catalytic activity is dispersed and resides within not only the loop sequence but also the surrounding protein architecture. This has broad implications for the general mechanistic understanding of enzyme reactions and the role that flexible loops play in the catalytic cycle.
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