Name
Title | ||
|---|---|---|
The Assembly-Inducing Laulimalide/Peloruside A Binding Site on Tubulin: Molecular Modeling and Biochemical Studies with [H]Peloruside A. |
Abstract | ||
|---|---|---|
We used synthetic peloruside A for the commercial preparation of [H-3]peloruside A. The radiolabeled compound bound to preformed tubulin polymer in amounts stoichiometric with the polymer's tubulin content, with an apparent K-d value of 0.35 mu M. A less active peloruside A analogue, (11-R)-peloruside A and laulimalide acted as competitive inhibitors of the binding of the [H-3]peloruside A, with apparent K-i values of 9.3 and 0.25 mu M, respectively. Paclitaxel, epothilone B, and discodermolide had essentially no ability to inhibit [H-3]peloruside A binding, confirming that these compounds bind to a different site on tubulin polymer. We modeled both laulimalide and peloruside A into the binding site on beta-tubulin that was identified by Huzil et al. (J. Mol. Biol. 2008, 378, 1016-1030), but our model provides a more reasonable structural basis for the protein-ligand interaction. There is a more complete desolvation of the peloruside A ligand and a greater array of favorable hydrophobic and electrostatic interactions exhibited by peloruside A at its beta-tubulin binding site. In addition, the protein architecture in our peloruside A binding model was suitable for binding laulimalide. With the generation of both laulimalide and peloruside A binding models, it was possible to delineate the structural basis for the greater activity of laulimalide relative to peloruside A and to rationalize the known structure-activity relationship data for both compounds. |
Year | DOI | Venue |
|---|---|---|
2010 | 10.1021/ci1002894 | JOURNAL OF CHEMICAL INFORMATION AND MODELING |
Keywords | Field | DocType |
binding sites,tubulin,stereoisomerism,tritium | Tubulin,Binding site,Ligand (biochemistry),Binding protein,Discodermolide,Ligand,Chemistry,Stereochemistry,Molecular model,Stereoisomerism | Journal |
Volume | Issue | ISSN |
50 | 11 | 1549-9596 |
Citations | PageRank | References |
1 | 0.48 | 0 |
Authors | ||
5 | ||
Name | Order | Citations | PageRank |
|---|---|---|---|
| Tam Luong Nguyen | 1 | 1 | 0.82 |
| Xiaoming Xu | 2 | 1 | 0.48 |
| Rick Gussio | 3 | 1 | 1.50 |
| Arun K Ghosh | 4 | 2 | 0.94 |
| Ernest Hamel | 5 | 1 | 0.82 |