Mapping the Nucleotide and Isoform-Dependent Structural and Dynamical Features of Ras Proteins

@article{citeulike:2880980, abstract = {Summary 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.}, author = {Gorfe, Alemayehu A. and Grant, Barry J. and Mccammon, Andrew J. }, citeulike-article-id = {2880980}, comment = {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- and active GTP-bound states remains unclear. Here Gorfe et al. combine sequence, structural and molecular dynamics analysis to quantitatively assess the structural and dynamical features of active and inactive states and details of their interconversion. Furthermore, the authors describe a number of isoform-specific long-range side chain interactions that define isoform specific pathways of communication between the nucleotide binding site and the C-terminal end of the protein essential for membrane attachment.}, doi = {http://dx.doi.org/10.1016/j.str.2008.03.009}, journal = {Structure}, keywords = {md\_simulation, mine, ntpases, pca, protein\_dynamics, protein\_structure, ras}, month = {June}, number = {6}, pages = {885--896}, posted-at = {2008-06-10 22:34:01}, priority = {0}, title = {Mapping the Nucleotide and Isoform-Dependent Structural and Dynamical Features of Ras Proteins}, url = {http://dx.doi.org/10.1016/j.str.2008.03.009}, volume = {16}, year = {2008} }

TY - JOUR ID - citeulike:2880980 L3 - citeulike-article-id:2880980 TI - Mapping the Nucleotide and Isoform-Dependent Structural and Dynamical Features of Ras Proteins JF - Structure VL - 16 IS - 6 SP - 885 EP - 896 N2 - Summary 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. KW - md_simulation KW - mine KW - ntpases KW - pca KW - protein_dynamics KW - protein_structure KW - ras N1 - 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- and active GTP-bound states remains unclear. Here Gorfe et al. combine sequence, structural and molecular dynamics analysis to quantitatively assess the structural and dynamical features of active and inactive states and details of their interconversion. Furthermore, the authors describe a number of isoform-specific long-range side chain interactions that define isoform specific pathways of communication between the nucleotide binding site and the C-terminal end of the protein essential for membrane attachment. AU - Gorfe, Alemayehu AU - Grant, Barry AU - Mccammon, Andrew PY - 2008/06/11/ UR - http://dx.doi.org/10.1016/j.str.2008.03.009 ER -