Matches in SemOpenAlex for { <https://semopenalex.org/work/W1152561206> ?p ?o ?g. }
- W1152561206 endingPage "4193" @default.
- W1152561206 startingPage "4179" @default.
- W1152561206 abstract "Likely due to conformational rearrangements, small molecule inhibitors may stabilize the active conformation of protein kinases and paradoxically promote tumorigenesis. We combined limited proteolysis with stable isotope labeling MS to monitor protein conformational changes upon binding of small molecules. Applying this method to the human serine/threonine kinase B-Raf, frequently mutated in cancer, we found that binding of ATP or its nonhydrolyzable analogue AMP-PNP, but not ADP, stabilized the structure of both B-Raf(WT) and B-Raf(V600E). The ATP-competitive type I B-Raf inhibitor vemurafenib and the type II inhibitor sorafenib stabilized the kinase domain (KD) but had distinct effects on the Ras-binding domain. Stabilization of the B-Raf(WT) KD was confirmed by hydrogen/deuterium exchange MS and molecular dynamics simulations. Our results are further supported by cellular assays in which we assessed cell viability and phosphorylation profiles in cells expressing B-Raf(WT) or B-Raf(V600E) in response to vemurafenib or sorafenib. Our data indicate that an overall stabilization of the B-Raf structure by specific inhibitors activates MAPK signaling and increases cell survival, helping to explain clinical treatment failure. We also applied our method to monitor conformational changes upon nucleotide binding of the pseudokinase KSR1, which holds high potential for inhibition in human diseases." @default.
- W1152561206 created "2016-06-24" @default.
- W1152561206 creator A5001032583 @default.
- W1152561206 creator A5015270508 @default.
- W1152561206 creator A5021890213 @default.
- W1152561206 creator A5027241504 @default.
- W1152561206 creator A5029344824 @default.
- W1152561206 creator A5031830453 @default.
- W1152561206 creator A5036331925 @default.
- W1152561206 creator A5038356859 @default.
- W1152561206 creator A5047840816 @default.
- W1152561206 creator A5055074092 @default.
- W1152561206 creator A5056332662 @default.
- W1152561206 creator A5072800163 @default.
- W1152561206 creator A5077048065 @default.
- W1152561206 creator A5086414502 @default.
- W1152561206 date "2015-08-25" @default.
- W1152561206 modified "2023-10-18" @default.
- W1152561206 title "Limited Proteolysis Combined with Stable Isotope Labeling Reveals Conformational Changes in Protein (Pseudo)kinases upon Binding Small Molecules" @default.
- W1152561206 cites W1561283795 @default.
- W1152561206 cites W1639582946 @default.
- W1152561206 cites W1969249762 @default.
- W1152561206 cites W1970845550 @default.
- W1152561206 cites W1971947883 @default.
- W1152561206 cites W1975131304 @default.
- W1152561206 cites W1977223471 @default.
- W1152561206 cites W1979222512 @default.
- W1152561206 cites W1979514203 @default.
- W1152561206 cites W1980690266 @default.
- W1152561206 cites W1985309852 @default.
- W1152561206 cites W1985821753 @default.
- W1152561206 cites W1989026274 @default.
- W1152561206 cites W1996962669 @default.
- W1152561206 cites W2003625237 @default.
- W1152561206 cites W2004295816 @default.
- W1152561206 cites W2011407333 @default.
- W1152561206 cites W2011780255 @default.
- W1152561206 cites W2012310626 @default.
- W1152561206 cites W2016819009 @default.
- W1152561206 cites W2018078143 @default.
- W1152561206 cites W2020513008 @default.
- W1152561206 cites W2021427887 @default.
- W1152561206 cites W2025439513 @default.
- W1152561206 cites W2030205108 @default.
- W1152561206 cites W2031903272 @default.
- W1152561206 cites W2034130551 @default.
- W1152561206 cites W2037303344 @default.
- W1152561206 cites W2047985610 @default.
- W1152561206 cites W2050481433 @default.
- W1152561206 cites W2050972073 @default.
- W1152561206 cites W2051165598 @default.
- W1152561206 cites W2052781279 @default.
- W1152561206 cites W2056924558 @default.
- W1152561206 cites W2057069307 @default.
- W1152561206 cites W2058322072 @default.
- W1152561206 cites W2059299367 @default.
- W1152561206 cites W2062896063 @default.
- W1152561206 cites W2065909963 @default.
- W1152561206 cites W2066736637 @default.
- W1152561206 cites W2067362253 @default.
- W1152561206 cites W2068436530 @default.
- W1152561206 cites W2070719504 @default.
- W1152561206 cites W2075758247 @default.
- W1152561206 cites W2077804275 @default.
- W1152561206 cites W2086235533 @default.
- W1152561206 cites W2086286404 @default.
- W1152561206 cites W2086778602 @default.
- W1152561206 cites W2089273088 @default.
- W1152561206 cites W2090342453 @default.
- W1152561206 cites W2093653062 @default.
- W1152561206 cites W2103080476 @default.
- W1152561206 cites W2106543129 @default.
- W1152561206 cites W2108268983 @default.
- W1152561206 cites W2109321699 @default.
- W1152561206 cites W2112369308 @default.
- W1152561206 cites W2114918609 @default.
- W1152561206 cites W2116978122 @default.
- W1152561206 cites W2123182960 @default.
- W1152561206 cites W2128542677 @default.
- W1152561206 cites W2131321938 @default.
- W1152561206 cites W2133258578 @default.
- W1152561206 cites W2134831715 @default.
- W1152561206 cites W2139213909 @default.
- W1152561206 cites W2142358502 @default.
- W1152561206 cites W2147024375 @default.
- W1152561206 cites W2154319440 @default.
- W1152561206 cites W2155009402 @default.
- W1152561206 cites W2156373035 @default.
- W1152561206 cites W2156495637 @default.
- W1152561206 cites W2158933105 @default.
- W1152561206 cites W2159765576 @default.
- W1152561206 cites W2160415437 @default.
- W1152561206 cites W2163188200 @default.
- W1152561206 cites W2164242115 @default.
- W1152561206 cites W2167617907 @default.
- W1152561206 cites W2168747115 @default.
- W1152561206 cites W2168822202 @default.
- W1152561206 cites W2169350343 @default.