Insights into the importance of WPD-loop sequence for activity and structure in protein tyrosine phosphatases

Shen, Ruidan; Crean, Rory; Olsen, Keith J.; Corbella, Marina; Calixto, Ana Rita; Richan, Teisha; Brandão, Tiago A. S.; Berry, Ryan D.; Tolman, Alex; Loria, J. Patrick; Johnson, Sean; Kamerlin, Shina Caroline Lynn; Hengge, Alvan C.

doi:10.1039/d2sc04135a

Cited by 25 publications

(59 citation statements)

References 99 publications

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“…The WPD loop of phosphatases is the active site feature that has been most directly connected to differences in catalytic activity between phosphatases. [43,[57][58][59][60][61] Sequence divergence in this region can lead to differences loop dynamics, which in turn impacts catalysis. Two proline residues found in PTP1B (Pro 185 and Pro 188), but not YopH, are reported to constrain the dynamics of the PTP1B WPD loop, potentially leading to its lower enzyme activity.…”

Section: Resultsmentioning

confidence: 99%

Mapping the chemical space of active-site targeted covalent ligands for protein tyrosine phosphatases

Hong

Johns

et al. 2022

Preprint

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Protein tyrosine phosphatases (PTPs) are an important class of enzymes that modulate essential cellular processes through protein dephosphorylation and are dysregulated in various disease states. There is demand for new compounds that target the active sites of these enzymes, for use as chemical tools to dissect their biological roles or as leads for the development of new therapeutics. In this study, we explore an array of electrophiles and fragment scaffolds to investigate the required chemical parameters for covalent inhibition of tyrosine phosphatases. Our analysis juxtaposes the intrinsic electrophilicity of these compounds with their potency against several classical PTPs, revealing chemotypes that inhibit tyrosine phosphatases while minimizing excessive, potentially non-specific reactivity. We also assess sequence divergence at key residues in PTPs to explain their differential susceptibility to covalent inhibition. We anticipate that our study will inspire new strategies to develop covalent probes and inhibitors for tyrosine phosphatases.

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Section: Resultsmentioning

confidence: 99%

Mapping the chemical space of active-site targeted covalent ligands for protein tyrosine phosphatases

Hong

Johns

et al. 2022

Preprint

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“…We have previously [60][61][62] performed molecular dynamics (MD) simulations of protein tyrosine phosphatase (PTP1B) in the phospho-enzyme intermediate state, which is the reactant state for the second, rate limiting cleavage step of the catalytic mechanism (Figure S1). In this study, we used our previously prepared structures (based on PDB ID: 6B90 63 ) to simulate both the closed and open conformations of the WPD-loop with the AMBER18 59 simulation package.…”

Section: Preparation and Simulation Of The Model Systemsmentioning

confidence: 99%

“…refs. [60][61][62][63][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108] , among many others). For PTP1B, we applied KIF to predict the key residues and interactions that are associated with the WPD-loops' conformational state, and compared our predictions to the aforementioned available experimental data.…”

Section: Differences In the Interaction Network For The Closed And Op...mentioning

confidence: 99%

“…This is an approximate classification, as the WPD-loop conformation can fall on a spectrum between "open" and "closed states", occupying multiple stable conformations along that spectrum. 62 However, such a simplified definition enabled us to perform binary classification using both the ML and statistical analysis modules, by first discarding any frames that were classified as "Neither" (348 of 10,000 frames) according to the aforementioned protocol. The results from the ML module reflected the same issue as was described for the PDZ3 domain (only describing some and not all of the key interactions/residues, see the Supplementary Results), so herein we focus on our results generated only from the statistical analysis module.…”

Section: Differences In the Interaction Network For The Closed And Op...mentioning

confidence: 99%

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KIF – Key Interactions Finder: A Program to Identify the Key Molecular Interactions that Regulate Protein Conformational Changes

Crean

Slusky

Kasson

et al. 2023

Preprint

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Simulation datasets of proteins (e.g., those generated by molecular dynamics simulations) are filled with information about how the non-covalent interaction network within a protein regulates the conformation and thus function of said protein. Most proteins contain thousands of non-covalent interactions, with most of these being largely irrelevant to any single conformational change. The ability to automatically process any protein simulation dataset to identify the non-covalent interactions that are strongly associated with a single, defined conformational change would be a highly valuable tool for the community. Furthermore, the insights generated from this tool could be applied to both basic research, in order to improve understanding of a mechanism of action, or for protein engineering, to identify candidate mutations to improve/alter the functionality of any given protein. The open-source Python package Key Interactions Finder (KIF) enables users to identify those non-covalent interactions that are strongly associated with any conformational change of interest for any protein simulated. KIF gives the user full control to define the conformational change of interest as either a continuous or categorical variable, and methods from statistics or machine learning can be applied to identify and rank the interactions and residues distributed throughout the protein which are relevant to the conformational change. Finally, KIF has been applied to three diverse model systems (protein tyrosine phosphatase 1B, the PDZ3 domain, and the KE07 series of Kemp eliminases) in order to showcase its power to identify key features that regulate functionally important conformational dynamics.

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“…The WPD loop of phosphatases is the active site feature that has been most directly connected to differences in catalytic activity between phosphatases. [43,[59][60][61][62][63] Sequence divergence in this region can lead to differences loop dynamics, which in turn impacts catalysis. Two proline residues found in PTP1B (Pro 185 and Pro 188), but not YopH, are reported to constrain the dynamics of the PTP1B WPD loop, potentially leading to its lower enzyme activity.…”

Section: Differences In Phosphatase Covalent Inhibition Are Dictated ...mentioning

confidence: 99%

Mapping the Chemical Space of Active‐Site Targeted Covalent Ligands for Protein Tyrosine Phosphatases**

Hong

Johns

et al. 2023

ChemBioChem

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Protein tyrosine phosphatases (PTPs) are an important class of enzymes that modulate essential cellular processes through protein dephosphorylation and are dysregulated in various disease states. There is demand for new compounds that target the active sites of these enzymes, for use as chemical tools to dissect their biological roles or as leads for the development of new therapeutics. In this study, we explore an array of electrophiles and fragment scaffolds to investigate the required chemical parameters for covalent inhibition of tyrosine phos-phatases. Our analysis juxtaposes the intrinsic electrophilicity of these compounds with their potency against several classical PTPs, revealing chemotypes that inhibit tyrosine phosphatases while minimizing excessive, potentially non-specific reactivity. We also assess sequence divergence at key residues in PTPs to explain their differential susceptibility to covalent inhibition. We anticipate that our study will inspire new strategies to develop covalent probes and inhibitors for tyrosine phosphatases.

show abstract

Insights into the importance of WPD-loop sequence for activity and structure in protein tyrosine phosphatases

Abstract: Protein tyrosine phosphatases (PTPs) possess a conserved mobile catalytic loop, the WPD-loop, which brings an aspartic acid into the active site where it acts as an acid/base catalyst. Prior experimental...

Cited by 25 publications

References 99 publications

Mapping the chemical space of active-site targeted covalent ligands for protein tyrosine phosphatases

Mapping the chemical space of active-site targeted covalent ligands for protein tyrosine phosphatases

KIF – Key Interactions Finder: A Program to Identify the Key Molecular Interactions that Regulate Protein Conformational Changes

Mapping the Chemical Space of Active‐Site Targeted Covalent Ligands for Protein Tyrosine Phosphatases**

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