Small-molecule and mutational analysis of allosteric Eg5 inhibition by monastrol

BMC Chemical Biology
Zoltan Maliga, Timothy J Mitchison

Abstract

A recent crystal structure of monastrol in a ternary complex with the kinesin Eg5 motor domain highlights a novel, induced-fit drug binding site at atomic resolution. Mutational obliteration of the monastrol binding site results in a monastrol-resistant, but otherwise catalytically active Eg5 motor domain. However, considering the conformational changes at this site, it is unclear what specific interactions stabilize the interaction between monastrol and the Eg5 motor domain. To study the molecular complementarity of the monastrol-Eg5 interaction, we used a combination of synthetic chemistry and targeted mutations in Eg5 to measure the contribution of specific contacts to inhibition of Eg5 in vitro and in cultured cells. Structure-activity data on chemical derivatives, sequence analysis of Eg5 homologs from different species, and the effect of mutations near the drug binding site were consistent with the crystal structure. The mechanism of monastrol revealed by our data rationalizes its specificity for Eg5 over other kinesins and highlights a potential mechanism of drug resistance for anti-cancer therapy targeting this site in Eg5.

References

May 9, 1995·Proceedings of the National Academy of Sciences of the United States of America·K E Sawin, T J Mitchison
Mar 8, 2000·Biochemistry·S C HopkinsI D Kuntz
May 10, 2000·Chemistry & Biology·B S DeDecker
Mar 10, 2001·The Journal of Cell Biology·K J VerheyB Margolis
Sep 21, 2001·The Journal of Cell Biology·T M Kapoor, T J Mitchison
Feb 14, 2002·Physiological Genomics·Ming-Chyuan ChenH William Detrich
Sep 27, 2002·Chemistry & Biology·Zoltan MaligaTimothy J Mitchison
Jan 15, 2003·Biochemistry·Salvatore DeBonisFrank Kozielski
Mar 15, 2003·Science·Aaron F StraightTimothy J Mitchison
Dec 16, 2003·Journal of Molecular Biology·Youwei YanLawrence C Kuo
May 6, 2004·Cancer Research·Roman SakowiczKenneth W Wood
Jun 9, 2004·Current Biology : CB·I M-T C CrevelR A Cross
Dec 8, 2004·The Journal of Cell Biology·David T MiyamotoTimothy J Mitchison
Jan 25, 2005·The Journal of Biological Chemistry·Jared C CochranSusan P Gilbert
Feb 8, 2005·Proceedings of the National Academy of Sciences of the United States of America·Ralf KittlerFrank Buchholz
May 6, 2005·Nature·Lukas C KapiteinChristoph F Schmidt
May 25, 2005·Chembiochem : a European Journal of Chemical Biology·Michael GartnerAthanassios Giannis

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Citations

Jun 19, 2013·Chromosoma·Anna-Leena Salmela, Marko J Kallio
Jan 22, 2009·Cancer Metastasis Reviews·Dennis HuszarRonald Herbst
Feb 23, 2011·Oncogene·A Janssen, R H Medema
Mar 14, 2012·Proceedings of the National Academy of Sciences of the United States of America·Lin TianLuke D Lavis
Apr 20, 2011·Dementia and Geriatric Cognitive Disorders·Kurt A Jellinger, Johannes Attems
Jul 30, 2014·The Journal of Cell Biology·Kara J Helmke, Rebecca Heald
Sep 12, 2007·The Journal of Cell Biology·Kenneth A Myers, Peter W Baas
Apr 20, 2016·The Journal of Cell Biology·Emma G SturgillRyoma Ohi
Sep 7, 2016·Naunyn-Schmiedeberg's Archives of Pharmacology·Lilian Areal MarquesMário Sérgio Mantovani
Jun 26, 2007·Bioorganic & Medicinal Chemistry·Emmanuel KleinLuc Lebeau
May 17, 2017·Genes, Chromosomes & Cancer·Yasamin AsbaghiKirk J McManus
Jun 25, 2017·Cytoskeleton·Kathleen G BickelPatricia Wadsworth
Mar 20, 2010·The Journal of Biological Chemistry·Elizabeth D KimSunyoung Kim
Jun 3, 2008·The Prostate·Norihiro HayashiMartin E Gleave
Sep 2, 2010·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Michael J F BarresiRolf O Karlstrom
Oct 16, 2013·Biology of the Cell·Joshua S Waitzman, Sarah E Rice
Nov 2, 2019·MedChemComm·Elena González-HernándezConcepción Pérez-Melero
Dec 4, 2010·The Journal of Biological Chemistry·Liqiong LiuEdward J Wojcik
Dec 12, 2013·Oncotarget·Prisca ExertierMartin Hagedorn
May 10, 2013·The Journal of Biological Chemistry·Hung Yi Kristal KaanSteven S Rosenfeld
Nov 9, 2012·The Journal of Biological Chemistry·Adeline GouletCarolyn A Moores
Apr 17, 2014·The Journal of Biological Chemistry·Liqiong LiuEdward J Wojcik
Feb 13, 2016·Chemical Biology & Drug Design·Wei ZhangYonghe Li
Aug 21, 2008·Cell Motility and the Cytoskeleton·Irina TikhonenkoMichael P Koonce
Dec 15, 2010·The Journal of Biological Chemistry·William M Behnke-ParksSteven S Rosenfeld
Sep 7, 2019·Molecular Cancer Therapeutics·Rose-Laure IndoratoDimitrios A Skoufias
Dec 15, 2020·Biochemical Pharmacology·Isabel Garcia-Saez, Dimitrios A Skoufias
Jul 27, 2007·Journal of Cell Science·Alex BanniganTobias I Baskin
Jul 3, 2021·International Journal of Molecular Sciences·Himanshu PandeyLarisa Gheber
Jan 5, 2011·The Journal of Physical Chemistry. B·Wei Zhang
Aug 30, 2007·Journal of Medicinal Chemistry·Cynthia A ParrishDashyant Dhanak

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Methods Mentioned

BETA
dissection
X-ray
PCR

Software Mentioned

PyMol

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