A Conserved Local Structural Motif Controls the Kinetics of PTP1B Catalysis.

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Protein tyrosine phosphatase 1B (PTP1B) is a key regulator of insulin and leptin signaling.
• PTP1B's catalytic activity depends on the WPD loop transitioning between open and closed states.
• The mechanism of this critical WPD loop transition has remained elusive.

Purpose of the Study:

• To elucidate the molecular mechanism of WPD loop conformational transitions in PTP1B.
• To identify key structural elements governing PTP1B catalytic competence.
• To explore the broader implications of these findings for other protein tyrosine phosphatases (PTPs) and related enzymes.

Main Methods:

• Atomically detailed molecular dynamics simulations.
• Long-timescale and weighted ensemble simulations.
• Bioinformatic analysis of conserved motifs.

Main Results:

• The PDFG motif within the WPD loop acts as the crucial conformational switch.
• Structural rearrangements of the PDFG motif are necessary and sufficient for open-closed state transitions.
• The PDFG motif's conformational switching stabilizes the catalytically competent open state.

Conclusions:

• The PDFG motif is essential for regulating PTP1B enzymatic activity.
• Conserved PDFG and DFG motifs may control conformational states across multiple protein families, including kinases and deiminases.
• This provides a novel mechanistic insight into enzyme regulation and potential therapeutic targeting.