The high-resolution X-ray structure of vinca-domain inhibitors of microtubules provides a rational approach for drug design.

FEBS Letters
Wu ChengyongWang Yuxi

Abstract

Tubulin vinca-domain ligands can inhibit microtubule polymerization, causing cell death in mitosis, and their potential against multiple cancer types has been demonstrated. However, due to drug resistance and toxicities, development of novel vinca-domain ligands is still needed. In this study, we determined the high-resolution crystal structures of vinorelbine, YXD, and Phomopsin A in complex with tubulin at 2.5 Å. Additionally, we recapitulated all previously published high-resolution crystal structures of the vinca binding site to reveal critical residues and the molecular mechanism of vinca-domain ligands interacting with tubulin. Furthermore, we designed putatively novel triazolopyrimidine derivatives by introducing secondary amine groups to establish salt-bridge and H-bond interactions with Asp179β1 and Asn329α2 . Our studies provided the structural basis for designing novel tubulin vinca-domain ligands.

References

Dec 1, 1996·Journal of Biomolecular NMR·R A LaskowskiJ M Thornton
Mar 30, 2001·The Journal of Biological Chemistry·E CharbautA Sobel
Apr 18, 2003·Nature·Joe Howard, Anthony A Hyman
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
May 27, 2005·Nature·Benoît GigantMarcel Knossow
Sep 13, 2008·EMBO Reports·Anthony CormierBenoît Gigant
Jan 10, 2009·Cancer Chemotherapy and Pharmacology·Carl F BeyerJames J Gibbons
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Feb 12, 2010·Nature Reviews. Cancer·Maria Kavallaris
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Garib N MurshudovAlexei A Vagin
Aug 8, 2012·Acta Crystallographica. Section D, Biological Crystallography·Fanomezana M RanaivosonMarcel Knossow
Jan 5, 2013·Science·Andrea E ProtaMichel O Steinmetz
Jul 28, 2013·Biochemical Pharmacology·Isabel Marzo, Javier Naval
May 17, 2014·Cancer Treatment Reviews·N C Miltenburg, W Boogerd
Aug 13, 2014·Proceedings of the National Academy of Sciences of the United States of America·Andrea E ProtaMichel O Steinmetz
Apr 17, 2015·Current Topics in Medicinal Chemistry·Chun-Ting LeeKeng-Shiang Huang
Dec 15, 2015·Molecular Pharmacology·Yuxi WangJinliang Yang
Apr 23, 2016·Nature Reviews. Molecular Cell Biology·Gary BorisyEva Nogales
May 20, 2016·Methods in Molecular Biology·Stefan Florian, Timothy J Mitchison
Jun 18, 2016·Bioorganic & Medicinal Chemistry Letters·Na Zhang, Hongtao Zhao
Nov 25, 2016·ACS Medicinal Chemistry Letters·Carolyn A LeverettChakrapani Subramanyam
Jun 6, 2017·Cell Chemical Biology·Gonzalo Sáez-CalvoJosé Fernando Díaz
Jul 1, 2017·The Journal of Alternative and Complementary Medicine : Research on Paradigm, Practice, and Policy·Zhaoxue LuTracy Hammerstrom
Jun 7, 2018·Trends in Cell Biology·Michel O Steinmetz, Andrea E Prota
Apr 14, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Steven CoatsJean-Charles Soria
Jul 30, 2019·Expert Opinion on Therapeutic Patents·Kashif HaiderAhmed Kamal
Aug 29, 2019·Journal of Chemical Information and Modeling·Süleyman Selim Çınaroğlu, Emel Timuçin

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