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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.
Acta Crystallographica Section D – Wiley
Published: Jan 1, 2017
Keywords: ; ; ; ; ; ; ;
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