dc.contributor |
Agència de Gestió d'Ajuts Universitaris i de Recerca |
dc.contributor.author |
Ortiz Sánchez, Juan Manuel |
dc.contributor.author |
Nichols, SE |
dc.contributor.author |
Sayyah, J |
dc.contributor.author |
Brown, JH |
dc.contributor.author |
McCammon, JA |
dc.contributor.author |
et al. |
dc.date.accessioned |
2013-06-20T13:46:56Z |
dc.date.available |
2013-06-20T13:46:56Z |
dc.date.created |
2012-06-13 |
dc.date.issued |
2012-07-16 |
dc.identifier.citation |
Ortiz-Sanchez JM, Nichols SE, Sayyah J, Brown JH, McCammon JA, et al. (2012) Identification of Potential Small Molecule Binding Pockets on Rho Family. PLoS ONE 7(7): e40809. doi:10.1371/journal.pone.0040809 |
dc.identifier.uri |
http://hdl.handle.net/2072/212451 |
dc.format.extent |
13 p. |
dc.language.iso |
eng |
dc.publisher |
Jens Kleinjung, MRC National Institute for Medical Research, United Kingdom |
dc.relation.ispartofseries |
Els ajuts de l'AGAUR;2009BP_A 00126 |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.rights |
|
dc.source |
RECERCAT (Dipòsit de la Recerca de Catalunya) |
dc.subject.other |
Kinesin |
dc.subject.other |
Rho guanine nucleotide binding protein |
dc.title |
Identification of potential small molecule binding pockets on Rho family GTPases |
dc.type |
info:eu-repo/semantics/article |
dc.type |
info:eu-repo/semantics/publishedVersion |
dc.embargo.terms |
cap |
dc.description.abstract |
Rho GTPases are conformational switches that control a wide variety of signaling pathways critical for eukaryotic cell
development and proliferation. They represent attractive targets for drug design as their aberrant function and deregulated
activity is associated with many human diseases including cancer. Extensive high-resolution structures (.100) and recent
mutagenesis studies have laid the foundation for the design of new structure-based chemotherapeutic strategies. Although
the inhibition of Rho signaling with drug-like compounds is an active area of current research, very little attention has been
devoted to directly inhibiting Rho by targeting potential allosteric non-nucleotide binding sites. By avoiding the nucleotide
binding site, compounds may minimize the potential for undesirable off-target interactions with other ubiquitous GTP and
ATP binding proteins. Here we describe the application of molecular dynamics simulations, principal component analysis,
sequence conservation analysis, and ensemble small-molecule fragment mapping to provide an extensive mapping of
potential small-molecule binding pockets on Rho family members. Characterized sites include novel pockets in the vicinity
of the conformationaly responsive switch regions as well as distal sites that appear to be related to the conformations of the
nucleotide binding region. Furthermore the use of accelerated molecular dynamics simulation, an advanced sampling
method that extends the accessible time-scale of conventional simulations, is found to enhance the characterization of
novel binding sites when conformational changes are important for the protein mechanism. |