5VPI

Crystal structure of human KRAS G12A mutant in complex with GTP

Summary for 5VPI

• Entry DOI: 10.2210/pdb5vpi/pdb
• Related: 5VP7 5VPY 5VPZ 5VQ0 5VQ1 5VQ2 5VQ6 5VQ8
• Descriptor: GTPase KRas, GUANOSINE-5'-TRIPHOSPHATE, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: oncogenic mutant, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Lipid-anchor ; Cytoplasmic side : P01116
• Total number of polymer chains: 2
• Total formula weight: 39910.70

Authors

Xu, S.,Long, B.,Boris, G.,Ni, S.,Kennedy, M.A. (deposition date: 2017-05-05, release date: 2017-12-06, Last modification date: 2024-03-13)

Primary citation

Xu, S.,Long, B.N.,Boris, G.H.,Chen, A.,Ni, S.,Kennedy, M.A.
Structural insight into the rearrangement of the switch I region in GTP-bound G12A K-Ras.
Acta Crystallogr D Struct Biol, 73:970-984, 2017

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.

PubMed: 29199977
DOI: 10.1107/S2059798317015418

Experimental method

X-RAY DIFFRACTION (1.62 Å)