PDBsum entry 1tvk

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protein ligands Protein-protein interface(s) links
Cell cycle, structural protein PDB id
Protein chains
412 a.a. *
426 a.a. *
* Residue conservation analysis
PDB id:
Name: Cell cycle, structural protein
Title: The binding mode of epothilone a on a,b-tubulin by electron crystallography
Structure: Tubulin alpha chain. Chain: a. Other_details: see remark 400. Tubulin beta chain. Chain: b. Other_details: see remark 400
Source: Bos taurus. Cattle. Organism_taxid: 9913. Organ: brain. Organ: brain
Authors: J.H.Nettles,H.Li,B.Cornett,J.M.Krahn,J.P.Snyder,K.H.Downing
Key ref:
J.H.Nettles et al. (2004). The binding mode of epothilone A on alpha,beta-tubulin by electron crystallography. Science, 305, 866-869. PubMed id: 15297674 DOI: 10.1126/science.1099190
29-Jun-04     Release date:   14-Sep-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q2HJ86  (TBA1D_BOVIN) -  Tubulin alpha-1D chain
452 a.a.
412 a.a.*
Protein chain
Pfam   ArchSchema ?
Q6B856  (TBB2B_BOVIN) -  Tubulin beta-2B chain
445 a.a.
427 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 11 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     protein complex   5 terms 
  Biological process     microtubule-based process   4 terms 
  Biochemical function     nucleotide binding     4 terms  


DOI no: 10.1126/science.1099190 Science 305:866-869 (2004)
PubMed id: 15297674  
The binding mode of epothilone A on alpha,beta-tubulin by electron crystallography.
J.H.Nettles, H.Li, B.Cornett, J.M.Krahn, J.P.Snyder, K.H.Downing.
The structure of epothilone A, bound to alpha,beta-tubulin in zinc-stabilized sheets, was determined by a combination of electron crystallography at 2.89 angstrom resolution and nuclear magnetic resonance-based conformational analysis. The complex explains both the broad-based epothilone structure-activity relationship and the known mutational resistance profile. Comparison with Taxol shows that the longstanding expectation of a common pharmacophore is not met, because each ligand exploits the tubulin-binding pocket in a unique and independent manner.
  Selected figure(s)  
Figure 3.
Fig. 3. Hydrogen bonding (violet) around EpoA in ß-TB. Oxygens from C1 to C7 engage in network H bonds with M-loop residues. The thiazole is anchored by His227. Disruption of primary or secondary hydrogen bonds would occur upon mutation of Ala^231, Thr274, Arg282, or Gln292 to other residues as observed in epothilone-resistant cells. Protein secondary structure for helices is shown in red, sheets in blue, and loops in yellow. The protein side chains are colored by atom type: white, C; red, O; and blue, N. The EpoA ligand is colored by atom type: orange, C; red, O; blue, N; and yellow, S.
Figure 4.
Fig. 4. An energy-optimized composite model of a fictionalized epothilone showing diverse features of the SARs in the context of the EC-derived model for TB and epothilone A. This single ligand structure docked into ß-tubulin incorporates functional group modifications from five different analog studies that individually produced the same or better potency than epothilone A, including effects caused by changes of functionality at C3 (CN), C9-C10 (C=C), C12-C13 (N-Bz-aziridine), C14 ((S)-Me), and 21 (SMe). (A) The experimental conformation and binding mode of 1 in Figs. 1, 2, 3 used as a modeling template to illustrate geometric compatibility (C9=C10, C14-Me), hydrogen bonds (C3-CN), and hydrophobic complementarity (aziridine phenyl, S21-Me) for the five derivatives. Colors on the translucent protein surface range from brown (hydrophobic) to blue (hydrophylic). The ligand is colored by atom type: white, C; red, O; blue, N; and yellow, S. (B) Topological representation of the composite model; red corresponds to the five centers of substitution relative to epothilone A.
  The above figures are reprinted by permission from the AAAs: Science (2004, 305, 866-869) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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MMHD [(S,E)-2-methyl-1-(2-methylthiazol-4-yl) hexa-1,5-dien-ol], a novel synthetic compound derived from epothilone, suppresses nuclear factor-kappaB-mediated cytokine expression in lipopolysaccharide-stimulated BV-2 microglia.
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Novel epothilone lactones by an unusual diversion of the Grubbs' metathesis reaction.
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20051810 S.Harichand-Herdt, and R.M.O'regan (2010).
Identifying subsets of metastatic breast cancer patients likely to benefit from treatment with the epothilone B analog ixabepilone.
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19087985 A.Hussain, R.S.DiPaola, A.D.Baron, C.S.Higano, N.S.Tchekmedyian, and A.R.Johri (2009).
Phase II trial of weekly patupilone in patients with castration-resistant prostate cancer.
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De(side chain) model of epothilone: bioconformer interconversions DFT study.
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Making epothilones fluoresce: design, synthesis, and biological characterization of a fluorescent n12-aza-epothilone (azathilone).
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Bone marrow CFU-GM and human tumor xenograft efficacy of three tubulin binding agents.
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Toward docking-based virtual screening for discovering antitubulin agents by targeting taxane and colchicine binding sites.
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Recent advances in the study of the bioactive conformation of taxol.
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Possible binding site for paclitaxel at microtubule pores.
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Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of beta-tubulin.
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Novel anti-tubulin cytotoxic agents for breast cancer.
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On and around microtubules: an overview.
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Biotransformation profiling of [(14)C]ixabepilone in human plasma, urine and feces samples using accelerator mass spectrometry (AMS).
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Promising novel cytotoxic agents and combinations in metastatic prostate cancer.
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A natural love of natural products.
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Microtubules: a dynamic target in cancer therapy.
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Epothilones in breast cancer: current status and future directions.
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A unique mode of microtubule stabilization induced by peloruside A.
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18663388 J.Young, and R.E.Taylor (2008).
Evolution of polyketides: post-PKS processing in the formation of spiroketals.
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Novel microtubule-targeting agents - the epothilones.
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The cloning and expression of alpha-tubulin in Monochamus alternatus.
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Application of epothilones in breast cancer therapy.
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17955508 M.M.Alhamadsheh, S.Gupta, R.A.Hudson, L.Perera, and L.M.Tillekeratne (2008).
Total synthesis and selective activity of a new class of conformationally restrained epothilones.
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18684060 M.Trivedi, I.Budihardjo, K.Loureiro, T.R.Reid, and J.D.Ma (2008).
Epothilones: a novel class of microtubule-stabilizing drugs for the treatment of cancer.
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Ixabepilone for the treatment of solid tumors: a review of clinical data.
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Ixabepilone (ixempra), a therapeutic option for locally advanced or metastatic breast cancer.
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New therapies for ovarian cancer: cytotoxics and molecularly targeted agents.
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19039362 Q.H.Chen, T.Ganesh, P.Brodie, C.Slebodnick, Y.Jiang, A.Banerjee, S.Bane, J.P.Snyder, and D.G.Kingston (2008).
Design, synthesis and biological evaluation of bridged epothilone D analogues.
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Ixabepilone for the treatment of taxane-refractory breast cancer.
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17315255 A.Lange, T.Schupp, F.Petersen, T.Carlomagno, and M.Baldus (2007).
High-resolution solid-state NMR structure of an anticancer agent.
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17347871 J.H.Beumer, R.C.Garner, M.B.Cohen, S.Galbraith, G.F.Duncan, T.Griffin, J.H.Beijnen, and J.H.Schellens (2007).
Human mass balance study of the novel anticancer agent ixabepilone using accelerator mass spectrometry.
  Invest New Drugs, 25, 327-334.  
  19455242 J.T.Huzil, K.Chen, L.Kurgan, and J.A.Tuszynski (2007).
The Roles of beta-Tubulin Mutations and Isotype Expression in Acquired Drug Resistance.
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17340668 K.H.Altmann, B.Pfeiffer, S.Arseniyadis, B.A.Pratt, and K.C.Nicolaou (2007).
The Chemistry and Biology of Epothilones-The Wheel Keeps Turning.
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Anticancer drugs from nature--natural products as a unique source of new microtubule-stabilizing agents.
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Cellular targets of natural products.
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17056728 P.Drabik, S.Gusarov, and A.Kovalenko (2007).
Microtubule stability studied by three-dimensional molecular theory of solvation.
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Synthesis and biological evaluation of (-)-dictyostatin and stereoisomers.
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Combined therapy of an established, highly aggressive breast cancer in mice with paclitaxel and a unique DNA-based cell vaccine.
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A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex.
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16941085 E.J.Carpenter, J.T.Huzil, R.F.Ludueña, and J.A.Tuszynski (2006).
Homology modeling of tubulin: influence predictions for microtubule's biophysical properties.
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Structural mechanisms underlying nucleotide-dependent self-assembly of tubulin and its relatives.
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Structure-activity relationships in side-chain-modified epothilone analogues--how important is the position of the nitrogen atom?
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Molecular design and chemical synthesis of a highly potent epothilone.
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The betaI/betaIII-tubulin isoforms and their complexes with antimitotic agents. Docking and molecular dynamics studies.
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Advantages of a unique DNA-based vaccine in comparison to paclitaxel in treatment of an established intracerebral breast cancer in mice.
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The tubulin-bound conformation of discodermolide derived by NMR studies in solution supports a common pharmacophore model for epothilone and discodermolide.
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The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.