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The Complete Molecular Analysis of PTP1B Function
Author(s) -
Pelletier Kristiane Torgeson,
Page Rebecca,
Peti Wolfgang
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.05372
Subject(s) - allosteric regulation , dephosphorylation , chemistry , rigidity (electromagnetism) , molecular dynamics , function (biology) , computational biology , biophysics , biochemistry , microbiology and biotechnology , phosphorylation , biology , enzyme , materials science , computational chemistry , phosphatase , composite material
Protein function originates from a cooperation of structural rigidity, dynamics at different timescales and allostery. Recently, we showed that PTP1B, a drug target for diabetes and cancer that catalyzes the dephosphorylation of numerous substrates in essential signaling pathways, uses both conformational and dynamic allostery to communicate between its allosteric and active sites. Further, we also discovered that the rigidity of the catalytically essential WPD loop is indispensable for PTP1B activity, demonstrating that both conformational rigidity and dynamics are essential for controlling protein activity. To determine if additional pockets distal from the active site may also influence PTP1B activity, we integrated bioinformatics analysis, activity assays, X‐ray crystallography and a broad variety of different NMR dynamics measurements. Our data revealed the presence of additional sites, distinct from the established allosteric pocket, which can potently alter PTP1B activity when perturbed. Our data suggest that that are a variety of ways to modulate the catalytic activity of PTP1B, and, in turn, may mitigate disorders due to PTP1B dysregulation, such as cancer. Support or Funding Information T32 GM008804