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Revisiting the structural flexibility of the complex p21(ras)-GTP: the catalytic conformation of the molecular switch

T A Soares1, J H Miller, T P Straatsma

  • 1Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington 99352, USA.

Proteins
|December 18, 2001
PubMed

Insights

GTP hydrolysis in p21(ras) protein causes shape changes, affecting cell signaling. Mutations in the Gln61 residue are common in human tumors, impacting protein function.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • The p21(ras) protein plays a crucial role in cellular signaling pathways, regulating cell growth and differentiation.
  • GTP hydrolysis by p21(ras) induces conformational changes essential for signal transduction.
  • Mutations in the Gln61 residue of p21(ras) are frequently observed in various human cancers, highlighting its importance in oncogenesis.

Purpose of the Study:

  • To investigate the conformational dynamics of the p21(ras) active site, focusing on the Gln61 residue.
  • To understand the molecular mechanisms underlying the transition between different p21(ras) conformations.
  • To provide insights into how Gln61 mutations may affect p21(ras) function and contribute to cancer development.

Main Methods:

  • Molecular dynamics simulations were performed on two independent structures of the GTP-bound uncomplexed p21(ras) enzyme.
  • Essential dynamics analysis was employed to characterize the key motions governing conformational transitions.
  • Simulated results were compared with previous studies on p21(ras) and its complex with p21-GAP.

Main Results:

  • Two distinct conformations of the GTP-bound p21(ras) enzyme were identified, differing in the orientation of the Gln61 side chain.
  • Essential dynamics analysis revealed specific motions associated with the transition between these conformations.
  • The observed conformational states provide a structural basis for understanding the functional implications of Gln61 mutations.

Conclusions:

  • The study elucidates the dynamic nature of the p21(ras) active site and the role of Gln61 in conformational regulation.
  • Understanding these dynamics is critical for comprehending how mutations in Gln61 contribute to aberrant signaling in cancer.
  • These findings may inform the development of targeted therapies for cancers harboring p21(ras) mutations.

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