The assembly-inducing laulimalide/peloruside a binding site on tubulin: molecular modeling and biochemical studies with [³H]peloruside A.
J Chem Inf Model
; 50(11): 2019-28, 2010 Nov 22.
Article
em En
| MEDLINE
| ID: mdl-21028850
We used synthetic peloruside A for the commercial preparation of [³H]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 µM. A less active peloruside A analogue, (11-R)-peloruside A and laulimalide acted as competitive inhibitors of the binding of the [³H]peloruside A, with apparent K(i) values of 9.3 and 0.25 µM, respectively. Paclitaxel, epothilone B, and discodermolide had essentially no ability to inhibit [³H]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 ß-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 ß-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Trítio
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Tubulina (Proteína)
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Modelos Moleculares
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Macrolídeos
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Compostos Bicíclicos Heterocíclicos com Pontes
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Multimerização Proteica
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Lactonas
Limite:
Animals
Idioma:
En
Revista:
J Chem Inf Model
Assunto da revista:
INFORMATICA MEDICA
/
QUIMICA
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
Estados Unidos