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A New Tubulin-Binding Site and Pharmacophore for Microtubule

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A New Tubulin-Binding Site and Pharmacophore for Microtubule A new tubulin-binding site and pharmacophore for SEE COMMENTARY microtubule-destabilizing anticancer drugs Andrea E. Protaa, Katja Bargstena, J. Fernando Diazb, May Marshc, Carmen Cuevasd, Marc Linigere, Christian Neuhause, Jose M. Andreub, Karl-Heinz Altmanne, and Michel O. Steinmetza,1 aDepartment of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland; bChemical and Physical Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas CIB-CSIC, 28040 Madrid, Spain; cSwiss Light Source, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland; dPharmaMar S.A., 28770 Madrid, Spain; and eDepartment of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zürich, 8093 Zürich, Switzerland Edited* by Susan Band Horwitz, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, and approved July 15, 2014 (received for review May 3, 2014) The recent success of antibody–drug conjugates (ADCs) in the Our data reveal a new tubulin-binding site and pharmacophore for treatment of cancer has led to a revived interest in microtubule- small molecules, and binding to this site is associated with a distinct destabilizing agents. Here, we determined the high-resolution molecular mechanism for the inhibition of microtubule formation. crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Results and Discussion Administration (FDA) for the treatment of advanced breast cancer. A New Tubulin-Binding Site for Structurally Diverse MDAs. We ini- We found that the drug binds to a site on β-tubulin that is distinct tially sought to investigate the molecular mechanism of action of from the vinca domain and that blocks the formation of longitu- rhizoxin. To provide insight into the binding mode of rhizoxin dinal tubulin interactions in microtubules. We also solved crystal with tubulin, we soaked crystals of a protein complex composed structures of tubulin in complex with both a variant of rhizoxin of two αβ-tubulin (T2), the stathmin-like protein RB3 (R), and and the phase 1 drug PM060184. Consistent with biochemical and tubulin tyrosine ligase (TTL; the complex is denoted T2R-TTL) mutagenesis data, we found that the two compounds bound to (17, 18) with the natural rhizoxin variant 2,3-desepoxy rhizoxin the same site as maytansine and that the structures revealed a com- (19) [referred to as “rhizoxin F” from here on (20); Fig. 1A] and mon pharmacophore for the three ligands. Our results delineate determined its tubulin-bound structure by X-ray crystallography a distinct molecular mechanism of action for the inhibition of micro- at 2.0-Å resolution (Fig. 1B and Table S1 and Fig. S1A). The tubule assembly by clinically relevant agents. They further provide overall structure of tubulin in the tubulin–rhizoxin F complex a structural basis for the rational design of potent microtubule- superimposed well with the one obtained in the absence of the destabilizing agents, thus opening opportunities for the develop- ligand (17) (rmsd, 0.124 Å over 354 Cα atoms). This result ment of next-generation ADCs for the treatment of cancer. suggests that binding of the compound does not affect the global conformation of the tubulin, although we cannot exclude that the drug mechanism | microtubule-targeting agents | X-ray crystallography BIOCHEMISTRY ligand may affect the conformation of the protein in its free state. More important, rhizoxin F was found to bind to a site on icrotubule-targeting agents such as the taxanes and the β-tubulin that is distinct from what is commonly referred to as Mvinca alkaloids represent a successful class of anticancer drugs (1). Vinblastine, for example, is a microtubule-destabiliz- Significance ing agent (MDA) that is widely used in combination therapy for the treatment of childhood and adult malignancies (2). The broad clinical application of MDAs, however, is hampered by Microtubules are dynamic protein filaments assembled from tu- their severe adverse effects (3). This problem has been very re- bulin subunits, which play a key role for cell division. Ligands that cently addressed by the use of antibody–drug conjugate (ADC) target microtubules and affect their dynamics belong to the most approaches, which have revived interest in the development of successful classes of chemotherapeutic drugs against cancer by highly potent MDAs for therapeutic use (4–6). inhibiting cell proliferation. Here we have analyzed three struc- For several important MDAs, the molecular mechanism of turally unrelated drugs that destabilize microtubules, using X-ray action on tubulin and microtubules has so far remained elusive. crystallography. The data reveal a new tubulin-binding site for Rhizoxin, for example, is a potent MDA that has been in- these drugs, which renders their mechanism of action distinct from vestigated in phase 2 clinical trials, but for reasons poorly un- that of other types of microtubule assembly inhibitors. Similar key derstood, it has demonstrated only very limited clinical efficacy interactions with tubulin are observed for all three ligands, thus (7). At the molecular level, it is well established that rhizoxin defining a common pharmacophore. Our results offer an oppor- interferes with the binding of vinblastine to tubulin; however, the tunity for the rational design of potent tubulin modulators for exact location of its binding site has been a matter of debate (8– the development of more efficient cancer therapies. 10). Interestingly, biochemical and mutagenesis data suggest that the structurally unrelated MDA maytansine (9, 11), which is part Author contributions: A.E.P., K.B., J.F.D., J.M.A., K.-H.A., and M.O.S. designed research; A.E.P., K.B., M.M., M.L., and C.N. performed research; C.C. contributed new reagents/ of an ADC that was recently approved by the FDA for the analytic tools; A.E.P., J.F.D., J.M.A., K.-H.A., and M.O.S. analyzed data; and A.E.P. and treatment of advanced breast cancer (11, 12), and the phase 1 drug M.O.S. wrote the paper with support from all the authors. PM060184 (13, 14) (Fig. 1A) share a common tubulin-binding site The authors declare no conflict of interest. with rhizoxin (9, 13, 14). These two latter drugs have also been *This Direct Submission article had a prearranged editor. reported to interfere with the binding of vinblastine; however, as Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, for rhizoxin, the exact binding sites and modes of action of may- www.pdb.org [PDB ID code 4TUY (T2R-TTL-rhizoxin F), 4TV9 (T2R-TTL-PM060184), 4TV8 tansine and PM060184 have not been elucidated (9, 14–16). (T2R-TTLmaytansine)]. To establish the exact tubulin-binding site of rhizoxin, may- See Commentary on page 13684. tansine, and PM060184 and to clarify their specific interactions 1To whom correspondence should be addressed. Email: [email protected]. with the protein, we have investigated the structures of the cor- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. responding ligand–tubulin complexes by X-ray crystallography. 1073/pnas.1408124111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1408124111 PNAS | September 23, 2014 | vol. 111 | no. 38 | 13817–13821 Downloaded by guest on September 23, 2021 Fig. 1. Structure of the tubulin–rhizoxin F complex. (A) Chemical structures of rhizoxin F, maytansine, and PM060184. (B) Overall view of the T2R-TTL– rhizoxin F complex. Tubulin (gray), RB3 (light green), and TTL (violet) are shown in ribbon representation; the MDA rhizoxin F (orange) and GDP (cyan) are depicted in spheres representation. As a reference, the vinblastine structure (yellow, PDB ID no. 1Z2B) is superimposed onto the T2R complex. (C) Overall view of the tubulin–rhizoxin F interaction in two different orientations. The tubulin dimer with bound ligand (α-tubulin-2 and β-tubulin-2 of the T2R-TTL–rhizoxin F complex) is shown in surface representation. The vinblastine structure is superimposed onto the β-tubulin chain to highlight the distinct binding site of rhizoxin F. All ligands are in sphere representation and are colored in orange (rhizoxin F), cyan (GDP), and yellow (vinblastine). (D) Close-up view of the interaction observed between rhizoxin F (orange sticks) and β-tubulin (gray ribbon). Interacting residues of β-tubulin are shown in stick representation and are labeled. the vinca domain, which is targeted by vinblastine (21–23) (Fig. residue in ligand binding, as revealed by our structures (Figs. 1D 1C). As shown in Fig. 1D, this pocket is adjacent to the guanine- and 2B). The acetylated nitrogen of the N-methyl alanine group nucleotide binding site and is shaped by hydrophobic and polar in maytansine (N2′) is solvent-exposed in the tubulin–maytansine residues of helices H3′, H11, and H11′, as well as the loops S3- complex, suggesting that the attachment of even bulkier sub- H3′ (T3-loop), S5-H5 (T5-loop), and H11-H11′ of β-tubulin. stituents to this atom should not interfere with the interactions of It has been previously suggested that the structurally distinct the maytansine macrocycle with the protein. This is in line with MDAs maytansine (9, 11) and PM060184 (13, 14) (Fig. 1A) the strong tubulin effects that have been observed for the may- share a common tubulin-binding site with rhizoxin (9, 13, 14); tansine derivatives S-methyl-DM1 and S-methyl-DM4 (26), however, both drugs were also reported to interfere with the which contain N2′-acyl moieties that are significantly larger than binding of vinblastine (9, 14–16). To clarify the exact binding site the natural acetyl group in maytansine. These findings suggest of maytansine and PM060184 on tubulin and their mode of in- that both derivatives bind to tubulin in a similar way as may- teraction with the protein, we solved tubulin structures in com- tansine; this should also hold true for lysine-Ne-MCC-DM1, the plex with either drug at 2.1- and 2.0-Å resolution, respectively, pharmacologically active, intracellular metabolite of the ADC using the same experimental approach as for rhizoxin F (Fig.
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