Structures of potent anticancer compounds bound to tubulin
Abstract
Abstract Small molecules that bind to tubulin exert powerful effects on cell division and apoptosis (programmed cell death). Cell‐based high‐throughput screening combined with chemo/bioinformatic and biochemical analyses recently revealed a novel compound MI‐181 as a potent mitotic inhibitor with heightened activity towards melanomas. MI‐181 causes tubulin depolymerization, activates the spindle assembly checkpoint arresting cells in mitosis, and induces apoptotic cell death. C2 is an unrelated compound previously shown to have lethal effects on microtubules in tumorigenic cell lines. We report 2.60 Å and 3.75 Å resolution structures of MI‐181 and C2, respectively, bound to a ternary complex of αβ‐tubulin, the tubulin‐binding protein stathmin, and tubulin tyrosine ligase. In the first of these structures, our crystallographic results reveal a unique binding mode for MI‐181 extending unusually deep into the well‐studied colchicine‐binding site on β‐tubulin. In the second structure the C2 compound occupies the colchicine‐binding site on β‐tubulin with two chemical moieties recapitulating contacts made by colchicine, in combination with another system of atomic contacts. These insights reveal the source of the observed effects of MI‐181 and C2 on microtubules, mitosis, and cultured cancer cell lines. The structural details of the interaction between tubulin and the described compounds may guide the developmentmore »
- Authors:
-
- Department of Chemistry and Biochemistry University of California, Los Angeles Los Angeles California 90095
- Department of Chemistry and Biochemistry University of California, Los Angeles Los Angeles California 90095, Molecular Biology Institute, University of California Los Angeles Los Angeles California 90095, Department of Energy Institute for Genomics and Proteomics University of California Los Angeles Los Angeles California 90095
- Department of Chemistry and Biochemistry University of California, Los Angeles Los Angeles California 90095, Molecular Biology Institute, University of California Los Angeles Los Angeles California 90095, Jonsson Comprehensive Cancer Center University of California Los Angeles Los Angeles California 90095
- Publication Date:
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1226512
- Alternate Identifier(s):
- OSTI ID: 1295972
- Grant/Contract Number:
- DE‐AC02–06CH11357
- Resource Type:
- Published Article
- Journal Name:
- Protein Science
- Additional Journal Information:
- Journal Name: Protein Science Journal Volume: 24 Journal Issue: 7; Journal ID: ISSN 0961-8368
- Publisher:
- Wiley Blackwell (John Wiley & Sons)
- Country of Publication:
- United Kingdom
- Language:
- English
Citation Formats
McNamara, Dan E., Senese, Silvia, Yeates, Todd O., and Torres, Jorge Z. Structures of potent anticancer compounds bound to tubulin. United Kingdom: N. p., 2015.
Web. doi:10.1002/pro.2704.
McNamara, Dan E., Senese, Silvia, Yeates, Todd O., & Torres, Jorge Z. Structures of potent anticancer compounds bound to tubulin. United Kingdom. https://doi.org/10.1002/pro.2704
McNamara, Dan E., Senese, Silvia, Yeates, Todd O., and Torres, Jorge Z. Wed .
"Structures of potent anticancer compounds bound to tubulin". United Kingdom. https://doi.org/10.1002/pro.2704.
@article{osti_1226512,
title = {Structures of potent anticancer compounds bound to tubulin},
author = {McNamara, Dan E. and Senese, Silvia and Yeates, Todd O. and Torres, Jorge Z.},
abstractNote = {Abstract Small molecules that bind to tubulin exert powerful effects on cell division and apoptosis (programmed cell death). Cell‐based high‐throughput screening combined with chemo/bioinformatic and biochemical analyses recently revealed a novel compound MI‐181 as a potent mitotic inhibitor with heightened activity towards melanomas. MI‐181 causes tubulin depolymerization, activates the spindle assembly checkpoint arresting cells in mitosis, and induces apoptotic cell death. C2 is an unrelated compound previously shown to have lethal effects on microtubules in tumorigenic cell lines. We report 2.60 Å and 3.75 Å resolution structures of MI‐181 and C2, respectively, bound to a ternary complex of αβ‐tubulin, the tubulin‐binding protein stathmin, and tubulin tyrosine ligase. In the first of these structures, our crystallographic results reveal a unique binding mode for MI‐181 extending unusually deep into the well‐studied colchicine‐binding site on β‐tubulin. In the second structure the C2 compound occupies the colchicine‐binding site on β‐tubulin with two chemical moieties recapitulating contacts made by colchicine, in combination with another system of atomic contacts. These insights reveal the source of the observed effects of MI‐181 and C2 on microtubules, mitosis, and cultured cancer cell lines. The structural details of the interaction between tubulin and the described compounds may guide the development of improved derivative compounds as therapeutic candidates or molecular probes to study cancer cell division.},
doi = {10.1002/pro.2704},
journal = {Protein Science},
number = 7,
volume = 24,
place = {United Kingdom},
year = {Wed May 27 00:00:00 EDT 2015},
month = {Wed May 27 00:00:00 EDT 2015}
}
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1002/pro.2704
https://doi.org/10.1002/pro.2704
Other availability
Search WorldCat to find libraries that may hold this journal
Cited by: 18 works
Citation information provided by
Web of Science
Web of Science
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.
Works referenced in this record:
Discovery of Cytotoxic Dolastatin 10 Analogues with N-Terminal Modifications
journal, December 2014
- Maderna, Andreas; Doroski, Matthew; Subramanyam, Chakrapani
- Journal of Medicinal Chemistry, Vol. 57, Issue 24
Identification of a Small Molecule That Induces Mitotic Arrest Using a Simplified High-Content Screening Assay and Data Analysis Method
journal, February 2006
- Wilson, Christopher J.; Si, Ying; Thompsons, Craig M.
- Journal of Biomolecular Screening, Vol. 11, Issue 1
Structural basis for the regulation of tubulin by vinblastine
journal, May 2005
- Gigant, Benoît; Wang, Chunguang; Ravelli, Raimond B. G.
- Nature, Vol. 435, Issue 7041
Linking Crystallographic Model and Data Quality
journal, May 2012
- Karplus, P. A.; Diederichs, K.
- Science, Vol. 336, Issue 6084
Chemical dissection of the cell cycle: probes for cell biology and anti-cancer drug development
journal, October 2014
- Senese, S.; Lo, Y. C.; Huang, D.
- Cell Death & Disease, Vol. 5, Issue 10
AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading
journal, January 2009
- Trott, Oleg; Olson, Arthur J.
- Journal of Computational Chemistry
Microtubules and resistance to tubulin-binding agents
journal, February 2010
- Kavallaris, Maria
- Nature Reviews Cancer, Vol. 10, Issue 3
Microtubules as a target for anticancer drugs
journal, April 2004
- Jordan, Mary Ann; Wilson, Leslie
- Nature Reviews Cancer, Vol. 4, Issue 4
Mitosis-targeted anti-cancer therapies: where they stand
journal, October 2012
- Chan, K-S; Koh, C-G; Li, H-Y
- Cell Death & Disease, Vol. 3, Issue 10
Developing novel C-4 analogues of pyrrole-based antitubulin agents: weak but critical hydrogen bonding in the colchicine site
journal, January 2013
- Da, Chenxiao; Telang, Nakul; Hall, Kayleigh
- MedChemComm, Vol. 4, Issue 2
The 4 Å X-Ray Structure of a Tubulin:Stathmin-like Domain Complex
journal, September 2000
- Gigant, Benoît; Curmi, Patrick A.; Martin-Barbey, Carole
- Cell, Vol. 102, Issue 6
Structural plasticity of tubulin assembly probed by vinca-domain ligands
journal, July 2012
- Ranaivoson, Fanomezana M.; Gigant, Benoît; Berritt, Simon
- Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 8
Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products
journal, July 2010
- Antonchick, Andrey P.; Gerding-Reimers, Claas; Catarinella, Mario
- Nature Chemistry, Vol. 2, Issue 9
Ligand identification using electron-density map correlations
journal, December 2006
- Terwilliger, Thomas C.; Adams, Paul D.; Moriarty, Nigel W.
- Acta Crystallographica Section D Biological Crystallography, Vol. 63, Issue 1
PHENIX : building new software for automated crystallographic structure determination
journal, October 2002
- Adams, Paul D.; Grosse-Kunstleve, Ralf W.; Hung, Li-Wei
- Acta Crystallographica Section D Biological Crystallography, Vol. 58, Issue 11
electronic Ligand Builder and Optimization Workbench ( eLBOW ): a tool for ligand coordinate and restraint generation
journal, September 2009
- Moriarty, Nigel W.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Acta Crystallographica Section D Biological Crystallography, Vol. 65, Issue 10
The Novel Microtubule-Destabilizing Drug BAL27862 Binds to the Colchicine Site of Tubulin with Distinct Effects on Microtubule Organization
journal, April 2014
- Prota, Andrea E.; Danel, Franck; Bachmann, Felix
- Journal of Molecular Biology, Vol. 426, Issue 8
A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs
journal, August 2014
- Prota, A. E.; Bargsten, K.; Diaz, J. F.
- Proceedings of the National Academy of Sciences, Vol. 111, Issue 38
Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model
journal, June 1985
- Dewar, Michael J. S.; Zoebisch, Eve G.; Healy, Eamonn F.
- Journal of the American Chemical Society, Vol. 107, Issue 13
Tools for integrated sequence-structure analysis with UCSF Chimera
journal, July 2006
- Meng, Elaine C.; Pettersen, Eric F.; Couch, Gregory S.
- BMC Bioinformatics, Vol. 7, Issue 1
Microtubule-binding agents: a dynamic field of cancer therapeutics
journal, October 2010
- Dumontet, Charles; Jordan, Mary Ann
- Nature Reviews Drug Discovery, Vol. 9, Issue 10
Stathmin Family Proteins Display Specific Molecular and Tubulin Binding Properties
journal, February 2001
- Charbaut, Elodie; Curmi, Patrick A.; Ozon, Sylvie
- Journal of Biological Chemistry, Vol. 276, Issue 19
XDS
journal, January 2010
- Kabsch, Wolfgang
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
Geometric characteristics of hydrogen bonds involving sulfur atoms in proteins
journal, July 2009
- Zhou, Peng; Tian, Feifei; Lv, Fenglin
- Proteins: Structure, Function, and Bioinformatics, Vol. 76, Issue 1
UCSF Chimera?A visualization system for exploratory research and analysis
journal, January 2004
- Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C.
- Journal of Computational Chemistry, Vol. 25, Issue 13
Dissecting cellular processes using small molecules: identification of colchicine-like, taxol-like and other small molecules that perturb mitosis
journal, April 2000
- Haggarty, Stephen J.; Mayer, Thomas U.; Miyamoto, David T.
- Chemistry & Biology, Vol. 7, Issue 4
Diversity-oriented synthesis as a tool for identifying new modulators of mitosis
journal, January 2014
- Ibbeson, Brett M.; Laraia, Luca; Alza, Esther
- Nature Communications, Vol. 5, Issue 1
The Binding of Vinca Domain Agents to Tubulin: Structural and Biochemical Studies
book, January 2010
- Cormier, Anthony; Knossow, Marcel; Wang, Chunguang
- Methods in Cell Biology
Phase I/IIa trial of the novel microtubule inhibitor BAL101553 in advanced solid tumors: Phase I completed.
journal, May 2014
- Molife, L. Rhoda; Imseeh, Georgios; Capelan, Marta
- Journal of Clinical Oncology, Vol. 32, Issue 15_suppl
Automated ligand fitting by core-fragment fitting and extension into density
journal, July 2006
- Terwilliger, Thomas C.; Klei, Herbert; Adams, Paul D.
- Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 8
RM1: A reparameterization of AM1 for H, C, N, O, P, S, F, Cl, Br, and I
journal, July 2006
- Rocha, Gerd B.; Freire, Ricardo O.; Simas, Alfredo M.
- Journal of Computational Chemistry, Vol. 27, Issue 10
Weak Nonbonded S···X (X = O, N, and S) Interactions in Proteins. Statistical and Theoretical Studies.
journal, July 2002
- Iwaoka, Michio; Takemoto, Shinya; Okada, Mai
- Bulletin of the Chemical Society of Japan, Vol. 75, Issue 7
15 Å Resolution Model of the Monomeric Kinesin Motor, KIF1A
journal, January 2000
- Kikkawa, Masahide; Okada, Yasushi; Hirokawa, Nobutaka
- Cell, Vol. 100, Issue 2
The contribution of αβ-tubulin curvature to microtubule dynamics
journal, November 2014
- Brouhard, Gary J.; Rice, Luke M.
- The Journal of Cell Biology, Vol. 207, Issue 3
Molecular Mechanism of Action of Microtubule-Stabilizing Anticancer Agents
journal, January 2013
- Prota, Andrea E.; Bargsten, Katja; Zurwerra, Didier
- Science, Vol. 339, Issue 6119
Variations in the colchicine-binding domain provide insight into the structural switch of tubulin
journal, August 2009
- Dorleans, A.; Gigant, B.; Ravelli, R. B. G.
- Proceedings of the National Academy of Sciences, Vol. 106, Issue 33
MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009
- Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
Coot model-building tools for molecular graphics
journal, November 2004
- Emsley, Paul; Cowtan, Kevin
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
Identification of Simple Compounds with Microtubule-Binding Activity That Inhibit Cancer Cell Growth with High Potency
journal, November 2011
- Yang, Wan Seok; Shimada, Kenichi; Delva, Darnelle
- ACS Medicinal Chemistry Letters, Vol. 3, Issue 1
Structure of a kinesin–tubulin complex and implications for kinesin motility
journal, July 2013
- Gigant, Benoît; Wang, Weiyi; Dreier, Birgit
- Nature Structural & Molecular Biology, Vol. 20, Issue 8
A designed ankyrin repeat protein selected to bind to tubulin caps the microtubule plus end
journal, July 2012
- Pecqueur, Ludovic; Duellberg, Christian; Dreier, Birgit
- Proceedings of the National Academy of Sciences, Vol. 109, Issue 30
Hydrogen-Bond Acceptor and Donor Properties of Divalent Sulfur ( Y -S- Z and R -S-H)
journal, August 1997
- Allen, F. H.; Bird, C. M.; Rowland, R. S.
- Acta Crystallographica Section B Structural Science, Vol. 53, Issue 4
Studies on Lysogenesis i.
journal, January 1951
- Bertani, G.
- Journal of Bacteriology, Vol. 62, Issue 3
High Content Screening of Diverse Compound Libraries Identifies Potent Modulators of Tubulin Dynamics
journal, February 2014
- Laraia, Luca; Stokes, Jamie; Emery, Amy
- ACS Medicinal Chemistry Letters, Vol. 5, Issue 5
Structural Basis of Microtubule Stabilization by Laulimalide and Peloruside A
journal, January 2014
- Prota, Andrea E.; Bargsten, Katja; Northcote, Peter T.
- Angewandte Chemie International Edition, Vol. 53, Issue 6
A TOG: -tubulin Complex Structure Reveals Conformation-Based Mechanisms for a Microtubule Polymerase
journal, August 2012
- Ayaz, P.; Ye, X.; Huddleston, P.
- Science, Vol. 337, Issue 6096
Refined structure of αβ-tubulin at 3.5 Å resolution 1 1Edited by I. A. Wilson
journal, November 2001
- Löwe, J.; Li, H.; Downing, K. H.
- Journal of Molecular Biology, Vol. 313, Issue 5
Structural insight into the inhibition of tubulin by vinca domain peptide ligands
journal, September 2008
- Cormier, Anthony; Marchand, Matthieu; Ravelli, Raimond B. G.
- EMBO reports, Vol. 9, Issue 11
Discovery of Novel 2-Aryl-4-benzoyl-imidazole (ABI-III) Analogues Targeting Tubulin Polymerization As Antiproliferative Agents
journal, August 2012
- Chen, Jianjun; Ahn, Sunjoo; Wang, Jin
- Journal of Medicinal Chemistry, Vol. 55, Issue 16
Hypervalent Nonbonded Interactions of a Divalent Sulfur Atom. Implications in Protein Architecture and the Functions
journal, June 2012
- Iwaoka, Michio; Isozumi, Noriyoshi
- Molecules, Vol. 17, Issue 6
Optimal description of a protein structure in terms of multiple groups undergoing TLS motion
journal, March 2006
- Painter, Jay; Merritt, Ethan A.
- Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 4
Structural Model for Tubulin Recognition and Deformation by Kinesin-13 Microtubule Depolymerases
journal, March 2013
- Asenjo, Ana B.; Chatterjee, Chandrima; Tan, Dongyan
- Cell Reports, Vol. 3, Issue 3
Structural basis of tubulin tyrosination by tubulin tyrosine ligase
journal, January 2013
- Prota, Andrea E.; Magiera, Maria M.; Kuijpers, Marijn
- The Journal of Cell Biology, Vol. 200, Issue 3
Structure of the αβ tubulin dimer by electron crystallography
journal, January 1998
- Nogales, Eva; Wolf, Sharon G.; Downing, Kenneth H.
- Nature, Vol. 391, Issue 6663
Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain
journal, March 2004
- Ravelli, Raimond B. G.; Gigant, Benoît; Curmi, Patrick A.
- Nature, Vol. 428, Issue 6979
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4