Structural impact of GTP binding on downstream KRAS signaling.

Chemical Science
Dóra K MenyhárdAndrás Perczel

Abstract

Oncogenic RAS proteins, involved in ∼30% of human tumors, are molecular switches of various signal transduction pathways. Here we apply a new protocol for the NMR study of KRAS in its (inactive) GDP- and (activated) GTP-bound form, allowing a comprehensive analysis of the backbone dynamics of its WT-, G12C- and G12D variants. We found that Tyr32 shows opposite mobility with respect to the backbone of its surroundings: it is more flexible in the GDP-bound form while more rigid in GTP-complexes (especially in WT- and G12D-GTP). Using the G12C/Y32F double mutant, we showed that the presence of the hydroxyl group of Tyr32 has a marked effect on the G12C-KRAS-GTP system as well. Molecular dynamics simulations indicate that Tyr32 is linked to the γ-phosphate of GTP in the activated states - an arrangement shown, using QM/MM calculations, to support catalysis. Anchoring Tyr32 to the γ-phosphate contributes to the capture of the catalytic waters participating in the intrinsic hydrolysis of GTP and supports a simultaneous triple proton transfer step (catalytic water → assisting water → Tyr32 → O1G of the γ-phosphate) leading to straightforward product formation. The coupled flip of negatively charged residues of switch I toward the insi...Continue Reading

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Citations

Mar 7, 2021·Biomolecules·Charles W Carter, Peter R Wills
Nov 26, 2020·The Analyst·Juan F AranedaChristopher Green
Aug 10, 2020·Cancer Metastasis Reviews·Zoltán Orgován, György M Keserű
Aug 21, 2020·Cancer Metastasis Reviews·Gyula PálfyAndrás Perczel

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Methods Mentioned

BETA
GTPases
nucleotide
GTPase
X-ray
NMR
nucleotide exchange
size exclusion chromatography

Software Mentioned

Modelfree
CARA
Maestro
FTMAP
GROMACS
Maestro Schrödinger Suite
- SPARKY
Jaguar
FAST
NMRFAM

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