title: Microsecond Timescale Dynamics of GDP-Bound Ras Underlies the Formation of Novel Inhibitor-Binding Pockets.
abstract: The recent discovery of inhibitory compounds binding to distinct pockets on GDP-bound Ras has renewed the view on the druggability of this crucial cancer driver. However, the origin of these pockets, which are not readily formed in the crystal structure in the absence of the compounds, is yet unclear. Herein, we explored the intrinsic flexibility of Ras⋅GDP on microsecond to millisecond timescales using relaxation-based NMR experiments, and identified substantial slow dynamics with τexof 34 μs at 5 °C, which maps to the regions showing a high level of correlation with those displaying conformational differences between the inhibitor-bound and free states. These findings, which have been demonstrated in both wild-type Ras and the oncogenic mutant (G12V), support the mechanism of extended conformational selection for Ras-inhibitor interactions where the small molecules redistribute the protein conformational ensemble favoring the final bound states.
authors.affiliation: School of Life Sciences, University of Science and Technology of China, 443 Huangshan Street, Hefei, Anhui, 230027, China.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Mao
authors.affiliation: School of Life Sciences, University of Science and Technology of China, 443 Huangshan Street, Hefei, Anhui, 230027, China.
authors.forename: Haijie
authors.initials: H
authors.lastname: Yao
authors.affiliation: School of Life Sciences, University of Science and Technology of China, 443 Huangshan Street, Hefei, Anhui, 230027, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Life Sciences, University of Science and Technology of China, 443 Huangshan Street, Hefei, Anhui, 230027, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Cheng
authors.affiliation: School of Life Sciences, University of Science and Technology of China, 443 Huangshan Street, Hefei, Anhui, 230027, China.|Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Dong
authors.identifier: 0000-0002-0705-5499
authors.initials: D
authors.lastname: Long
keywords: NMR spectroscopy; Ras; inhibitor-binding pockets; molecular recognition; protein dynamics