2021
DOI: 10.1021/jacs.0c11806
|View full text |Cite|
|
Sign up to set email alerts
|

Loop Dynamics and Enzyme Catalysis in Protein Tyrosine Phosphatases

Abstract: Protein tyrosine phosphatases (PTPs) play an important role in cellular signaling and have been implicated in human cancers, diabetes, and obesity. Despite shared catalytic mechanisms and transition states for the chemical steps of catalysis, catalytic rates within the PTP family vary over several orders of magnitude. These rate differences have been implied to arise from differing conformational dynamics of the closure of a protein loop, the WPD-loop, which carries a catalytically critical residue. The presen… Show more

Help me understand this report
View preprint versions

Search citation statements

Order By: Relevance

Paper Sections

Select...
3
1
1

Citation Types

11
152
0

Year Published

2021
2021
2024
2024

Publication Types

Select...
5
1

Relationship

1
5

Authors

Journals

citations
Cited by 72 publications
(163 citation statements)
references
References 88 publications
(233 reference statements)
11
152
0
Order By: Relevance
“…Monitoring of the root-mean-square deviation (RMSD) values allowed us to conclude that the protein readily reached an equilibrium state after approximately 50 ns, with a mean value of around 1.8 Å (Figure 4). Furthermore, a root-meansquare fluctuation (RMSF) plot for Cα did not show significantly high values, except for those residues located in the α7 helix, as previously observed in the literature [3,41].…”
Section: Computational Designsupporting
confidence: 77%
See 2 more Smart Citations
“…Monitoring of the root-mean-square deviation (RMSD) values allowed us to conclude that the protein readily reached an equilibrium state after approximately 50 ns, with a mean value of around 1.8 Å (Figure 4). Furthermore, a root-meansquare fluctuation (RMSF) plot for Cα did not show significantly high values, except for those residues located in the α7 helix, as previously observed in the literature [3,41].…”
Section: Computational Designsupporting
confidence: 77%
“…As an example, a considerable number of clinically approved inhibitory drugs, especially in oncology are molecules target kinases [2] . However, despite their potential to treat some diseases, protein phosphatases currently remain “undruggable”, therefore research in the field of phosphatase inhibition and mechanistic studies is of great interest for the scientific community [3–5] . I this regard, a phosphatase described by Tonks et al.…”
Section: Introductionmentioning
confidence: 99%
See 1 more Smart Citation
“…This includes recent computational studies of WPD-loop dynamics in wildtype PTP1B and YopH. 18 However, such studies are far from computationally trivial. In addition, while relevant NMR data exist that quantify the population difference between the two states in the wild-type enzymes, 17 these differences are both quite subtle (in the range of 1−2 kcal mol −1 depending on whether a ligand is bound or not, making them hard to quantify computationally), and there also do not exist analogous data for the substituted variants studied in this work.…”
Section: Computational Investigations Into the Origin Of The Implied Population Shiftsmentioning
confidence: 99%
“…Interestingly, the corresponding T177G variant of PTP1B shows a more modest effect and in the opposite direction. The documented correlation between WPD-loop dynamics and catalysis in YopH and PTP1B 17,18 provides a rationale for the altered pH dependencies of these variants.…”
Section: ■ Introductionmentioning
confidence: 98%