Back to Search
Start Over
Distinct Pose of Discodermolide in Taxol Binding Pocket Drives a Complementary Mode of Microtubule Stabilization
- Source :
- Biochemistry. 48:11664-11677
- Publication Year :
- 2009
- Publisher :
- American Chemical Society (ACS), 2009.
-
Abstract
- The microtubule cytoskeleton has proven to be an effective target for cancer therapeutics. One class of drugs, known as microtubule stabilizing agents (MSAs), binds to microtubule polymers and stabilizes them against depolymerization. The prototype of this group of drugs, Taxol, is an effective chemotherapeutic agent used extensively in the treatment of human ovarian, breast, and lung carcinomas. Although electron crystallography and photoaffinity labeling experiments determined that the binding site for Taxol is in a hydrophobic pocket in beta-tubulin, little was known about the effects of this drug on the conformation of the entire microtubule. A recent study from our laboratory utilizing hydrogen-deuterium exchange (HDX) in concert with various mass spectrometry (MS) techniques has provided new information on the structure of microtubules upon Taxol binding. In the current study we apply this technique to determine the binding mode and the conformational effects on chicken erythrocyte tubulin (CET) of another MSA, discodermolide, whose synthetic analogues may have potential use in the clinic. We confirmed that, like Taxol, discodermolide binds to the taxane binding pocket in beta-tubulin. However, as opposed to Taxol, which has major interactions with the M-loop, discodermolide orients itself away from this loop and toward the N-terminal H1-S2 loop. Additionally, discodermolide stabilizes microtubules mainly via its effects on interdimer contacts, specifically on the alpha-tubulin side, and to a lesser extent on interprotofilament contacts between adjacent beta-tubulin subunits. Also, our results indicate complementary stabilizing effects of Taxol and discodermolide on the microtubules, which may explain the synergy observed between the two drugs in vivo.
- Subjects :
- Paclitaxel
Binding pocket
macromolecular substances
Biology
Microtubules
Biochemistry
Microtubule stabilization
Article
Lactones
chemistry.chemical_compound
Tubulin
Microtubule
Alkanes
Animals
Protein Isoforms
Binding site
Binding Sites
Photoaffinity labeling
Protein Stability
Electron crystallography
Deuterium Exchange Measurement
Drug Synergism
Discodermolide
Peptide Fragments
Tubulin Modulators
chemistry
Pyrones
Biophysics
biology.protein
Cattle
Carbamates
Chickens
Dimerization
Protein Binding
Subjects
Details
- ISSN :
- 15204995 and 00062960
- Volume :
- 48
- Database :
- OpenAIRE
- Journal :
- Biochemistry
- Accession number :
- edsair.doi.dedup.....c72b44227abe1d821da56ddc8830f50b