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PAK4 crystal structures suggest unusual kinase conformational movements
Eric Y Zhang1, Byung Hak Ha1, Titus J Boggon2
1Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520, United States.
Biochimica Et Biophysica Acta. Proteins and Proteomics
|October 11, 2017
Summary
Protein kinases regulate cell signaling by opening and closing their catalytic cleft. This study reveals novel conformational changes in p21-activated kinase 4 (PAK4), suggesting diverse kinase regulation mechanisms.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Protein kinases are crucial signaling proteins and significant drug targets.
- Understanding kinase regulation is vital for basic research and clinical applications.
- Kinase hinging, the opening/closing of sub-domains for nucleotide exchange, is critical for regulation.
Purpose of the Study:
- To investigate the conformational dynamics of serine-threonine kinase, p21-activated kinase 4 (PAK4).
- To identify and characterize novel hinging motions and conformational states in PAK4.
- To explore the implications of observed conformational changes for kinase regulation diversity.
Main Methods:
- Analysis of 28 crystal structures of PAK4, including three newly determined structures.
- Determination of new crystal structures of PAK4 in complex with staurosporine, FRAX486, and fasudil.
- Principal component analysis (PCA) and hydrophobic spine analysis of PAK4 crystal structures.
Main Results:
- Identified unusual N-lobe and C-lobe motion in PAK4 involving partial unwinding of helix αC.
- Classified PAK4 crystal structures into three major conformational states using PCA.
- Observed concerted movements in kinase hydrophobic spines creating an accessible back pocket cavity.
Conclusions:
- PAK4 exhibits distinct conformational changes differing from previously described kinase motions.
- The observed movements suggest a potential diversity in kinase conformational changes and regulatory mechanisms.
- Findings contribute to a deeper understanding of protein kinase regulation and potential drug targeting.