PDBsum entry: 1tvk

Cell cycle, structural protein

PDB id: 1tvk

Contents

Protein chains

412 a.a. *

426 a.a. *

Ligands

GDP

GTP

_EP

* Residue conservation analysis

PDB id:

1tvk

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

Date:

29-Jun-04 Release date: 14-Sep-04

Protein chain

Q2HJ86  (TBA1D_BOVIN) -  Tubulin alpha-1D chain

Seq: 452 a.a.

Struc: 412 a.a.*

Protein chain

Q6B856  (TBB2B_BOVIN) -  Tubulin beta-2B chain

Seq: 445 a.a.

Struc: 427 a.a.*

* PDB and UniProt seqs differ at 11 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 

• Cellular component: protein complex (4 terms)
• Biological process: microtubule-based process (5 terms)
• Biochemical function: structural molecule activity (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.

ABSTRACT

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.