Nucleotide-Specific Autoinhibition of Full-Length K-Ras4B Identified by Extensive Conformational Sampling

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• K-Ras is a frequently mutated oncogene central to cancer development.
• K-Ras regulates cell signaling through GDP-GTP binding and conformational changes.
• The hypervariable region (HVR) of K-Ras plays a crucial role in its function.

Purpose of the Study:

• To map the interaction patterns between the K-Ras catalytic domain and its HVR.
• To understand how these interactions differ between the GDP-bound and GTP-bound states.
• To elucidate the structural basis of K-Ras regulation.

Main Methods:

• Molecular Dynamics with excited Normal Modes (MDeNM) simulations were employed.
• Simulations were initiated from an extended HVR conformation for both GDP- and GTP-bound K-Ras.
• Interaction patterns between the catalytic domain and HVR were analyzed without prior constraints.

Main Results:

• Similar K-Ras HVR-catalytic domain interaction patterns were observed in both GDP- and GTP-bound states.
• In the GDP-bound state, HVR interactions favor autoinhibition of the catalytic site.
• In the GTP-bound state, HVR interactions shift to overlap with the dimerization interface, facilitating signaling.

Conclusions:

• The K-Ras HVR dynamically interacts with the catalytic domain, modulating K-Ras activity.
• Nucleotide binding (GDP vs. GTP) dictates distinct HVR interaction modes, influencing K-Ras signaling output.
• These findings provide structural insights into K-Ras regulation and its role in oncogenesis.