Abstract
The ras oncogene products (H-Ras, K-Ras, and N-Ras) have been regarded as some of the most promising targets for anticancer drug discovery because their activating mutations are frequently found in human cancers. Nonetheless, molecular targeted therapy for them is currently unavailable. Here, we report the discovery of a small-molecule compound carrying a naphthalene ring, named KBFM123, which binds to the GTP-bound form of H-Ras. The solution structure of its complex with the guanosine 5'-(β,γ-imide) triphosphate-bound form of H-RasT35S (H-RasT35S·GppNHp) indicates that the naphthalene ring of KBFM123 interacts directly with a hydrophobic pocket located between switch I and switch II and allosterically inhibits the effector interaction by inducing conformational changes in switch I and its flanking region in strand β2, which are directly involved in recognition of the effector molecules, including c-Raf-1. In particular, Asp38 of H-Ras, a crucial residue for the interaction with c-Raf-1 via the formation of a salt bridge with Arg89 of the Ras-binding domain (RBD) of c-Raf-1, shows a drastic conformational change: its side chain orients toward the opposite direction. Consistent with these results, KBFM123 exhibits an activity t...Continue Reading
References
Jun 1, 1992·Protein Science : a Publication of the Protein Society·S G HybertsG Wagner
Sep 21, 1989·Nature·E F PaiA Wittinghofer
Dec 1, 1983·Biopolymers·W Kabsch, C Sander
Jun 15, 1995·Nature·N NassarA Wittinghofer
Nov 1, 1995·Journal of Biomolecular NMR·F DelaglioA Bax
Mar 1, 1996·Nature Structural Biology·C BlockA Wittinghofer
Feb 1, 1996·Journal of Molecular Graphics·R KoradiK Wüthrich
Aug 13, 1996·Biochemistry·M GeyerH R Kalbitzer
Dec 1, 1996·Journal of Biomolecular NMR·R A LaskowskiJ M Thornton
Jun 17, 1998·Nature Structural Biology·L HuangS H Kim
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Jan 4, 2001·Cell·M E PacoldR L Williams
Apr 26, 2001·Proceedings of the National Academy of Sciences of the United States of America·M SpoernerA Wittinghofer
Nov 10, 2001·Science·I R Vetter, A Wittinghofer
Dec 14, 2006·Acta Crystallographica. Section D, Biological Crystallography·Gerard J Kleywegt
Feb 17, 2007·The FEBS Journal·Michael SpoernerHans Robert Kalbitzer
Feb 23, 2008·Biochemical and Biophysical Research Communications·Jingling LiaoTohru Kataoka
Jun 24, 2008·Nature Reviews. Molecular Cell Biology·Antoine E Karnoub, Robert A Weinberg
May 19, 2010·The Journal of Biological Chemistry·Fumi ShimaTohru Kataoka
Oct 13, 2010·The Journal of Biological Chemistry·Michael SpoernerHans Robert Kalbitzer
Sep 21, 2011·The Journal of Biological Chemistry·Mitsugu ArakiAtsuo Tamura
Mar 21, 2012·Proceedings of the National Academy of Sciences of the United States of America·Till MaurerGuowei Fang
May 9, 2012·Angewandte Chemie·Qi SunStephen W Fesik
May 1, 2013·Proceedings of the National Academy of Sciences of the United States of America·Fumi ShimaTohru Kataoka
Aug 5, 2014·Journal of Biomolecular NMR·Qi SunStephen W Fesik
Feb 17, 2015·Structure·Susan K FeticsCarla Mattos
May 18, 2016·Scientific Reports·Shigeyuki MatsumotoFumi Shima
Citations
Aug 31, 2019·Biomolecular NMR Assignments·Gyula PálfyAndrás Perczel
Oct 11, 2019·Biological Chemistry·Raphael Gasper, Fred Wittinghofer
Aug 18, 2020·Journal of Biomolecular NMR·Christopher B MarshallMitsuhiko Ikura
Sep 16, 2020·Physical Chemistry Chemical Physics : PCCP·Jianzhong ChenWeiliang Zhu
Jan 27, 2019·Angewandte Chemie·Xiaomin ChenDong Long
Nov 4, 2020·Chembiochem : a European Journal of Chemical Biology·Xiaomin ChenDong Long
Apr 4, 2020·Molecular Cancer Therapeutics·Lihua ShuZhuo G Chen
Apr 18, 2020·The Journal of Physical Chemistry Letters·Dan LiuDong Long