5VQ2

Structural insight into the rearrangement of the switch I region in GTP-bound G12A K-Ras.

(2017) Acta Crystallogr D Struct Biol 73: 970-984

• PubMed: 29199977 Search on PubMed
• DOI: https://doi.org/10.1107/S2059798317015418
• Primary Citation of Related Structures:  
  5VP7, 5VPI, 5VPY, 5VPZ, 5VQ0, 5VQ1, 5VQ2, 5VQ6, 5VQ8, 5W22


• PubMed Abstract: 
  

  K-Ras, a molecular switch that regulates cell growth, apoptosis and metabolism, is activated when it undergoes a conformation change upon binding GTP and is deactivated following the hydrolysis of GTP to GDP. Hydrolysis of GTP in water is accelerated by coordination to K-Ras, where GTP adopts a high-energy conformation approaching the transition state. The G12A mutation reduces intrinsic K-Ras GTP hydrolysis by an unexplained mechanism. Here, crystal structures of G12A K-Ras in complex with GDP, GTP, GTPγS and GppNHp, and of Q61A K-Ras in complex with GDP, are reported. In the G12A K-Ras-GTP complex, the switch I region undergoes a significant reorganization such that the Tyr32 side chain points towards the GTP-binding pocket and forms a hydrogen bond to the GTP γ-phosphate, effectively stabilizing GTP in its precatalytic state, increasing the activation energy required to reach the transition state and contributing to the reduced intrinsic GTPase activity of G12A K-Ras mutants.

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Organizational Affiliation: 

Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA.