6ASE

KRAS mutant-A59G in GDP-bound

6ASE の概要

• エントリーDOI: 10.2210/pdb6ase/pdb
• 関連するPDBエントリー: 6ASA
• 分子名称: GTPase KRas, MAGNESIUM ION, GUANOSINE-5'-DIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: kras mutant a59g-gdp state, hydrolase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane ; Lipid-anchor ; Cytoplasmic side : P01116
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19782.29

構造登録者

Westover, K.,Lu, J. (登録日: 2017-08-24, 公開日: 2018-01-24, 最終更新日: 2023-10-04)

主引用文献

Lu, J.,Bera, A.K.,Gondi, S.,Westover, K.D.
KRAS Switch Mutants D33E and A59G Crystallize in the State 1 Conformation.
Biochemistry, 57:324-333, 2018

PubMed Abstract: KRAS switch loop movements play a crucial role in regulating RAS signaling, and alteration of these sensitive dynamics is a principal mechanism through which disease-associated RAS mutations lead to aberrant RAS activation. Prior studies suggest that despite a high degree of sequence similarity, the switches in KRAS are more dynamic than those in HRAS. We determined X-ray crystal structures of the rare tumorigenic KRAS mutants KRAS, in switch 1 (SW1), and KRAS, in switch 2 (SW2), bound to GDP and found these adopt nearly identical, open SW1 conformations as well as altered SW2 conformations. KRAS bound to a GTP analogue crystallizes in the same conformation. This open conformation is consistent with the inactive "state 1" previously observed for HRAS bound to GTP. For KRAS, switch rearrangements may be regulated by increased flexibility in the DXXGQ motif at codon 59. However, loss of interactions between side chains at codons 33 and 35 in the SW1 DPT motif drives changes for KRAS. The DPT motif is conserved for multiple members of the RAS subfamily but is not found in RAB, RHO, ARF, or Gα families, suggesting that dynamics mediated by this motif may be important for determining the selectivity of RAS-effector interactions. Biochemically, the consequence of altered switch dynamics is the same, showing impaired interaction with the guanine exchange factor SOS and loss of GAP-dependent GTPase activity. However, interactions with the RBD of RAF are preserved. Overall, these observations add to a body of evidence suggesting that HRAS and KRAS show meaningful differences in functionality stemming from differential protein dynamics independent of the hypervariable region.

PubMed: 29235861
DOI: 10.1021/acs.biochem.7b00974

実験手法

X-RAY DIFFRACTION (1.554 Å)