Journal
STRUCTURE
Volume 16, Issue 6, Pages 885-896Publisher
CELL PRESS
DOI: 10.1016/j.str.2008.03.009
Keywords
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Funding
- FIC NIH HHS [R03 TW007318, R03 TW007318-01A2, R03 TW000768-02, R03 TW007318-02] Funding Source: Medline
- Howard Hughes Medical Institute Funding Source: Medline
- NCRR NIH HHS [P41 RR008605-110052, P41 RR008605, P41 RR006009-150315, P41 RR008605-128884, P41 RR008605-147697, P41 RR008605-120018, P41 RR008605-138229] Funding Source: Medline
- NIGMS NIH HHS [R01 GM031749-14, R01 GM031749-25, R01 GM031749-24, R01 GM031749-21, R01 GM031749-26, R01 GM031749-20, R01 GM031749, R01 GM031749-22, R01 GM031749-18, R01 GM031749-23, R01 GM031749-19] Funding Source: Medline
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Ras GTPases are conformational switches controlling cell proliferation, differentiation, and development. Despite their prominent role in many forms of cancer, the mechanism of conformational transition between inactive GDP-bound and active GTP-bound states remains unclear. Here we describe a detailed analysis of available experimental structures and molecular dynamics simulations to quantitatively assess the structural and dynamical features of active and inactive states and their interconversion. We demonstrate that GTP-bound and nucleotide-free G12V H-ras sample a wide region of conformational space, and show that the inactive-to-active transition is a multiphase process defined by the relative rearrangement of the two switches and the orientation of Tyr32. We also modeled and simulated N- and K-ras proteins and found that K-ras is more flexible than N- and H-ras. We identified a number of isoform-specific, long-range side chain interactions that define unique pathways of communication between the nucleotide binding site and the C terminus.
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