WeNMR: Structural Biology on the Grid

Wassenaar, Tsjerk A.; Dijk, Marc van; Loureiro-Ferreira, Nuno; Schot, Gijs van der; Vries, Sjoerd J. de; Schmitz, Christophe; Zwan, J. van der; Boelens, Rolf; Giachetti, Andrea; Ferella, Lucio; Rosato, Antonio; Bertini, Ivano; Herrmann, Torsten; Jonker, Hendrik R. A.; Bagaria, Anurag; Jaravine, Victor; Güntert, Peter; Schwalbe, Harald; Vranken, Wim; Doreleijers, Jurgen F.; Vriend, Gert; Vuister, Geerten W.; Franke, Daniel; Kikhney, Alexey; Svergun, Dmitri I.; Fogh, Rasmus H.; Ionides, John; Laue, Ernest D.; Spronk, Chris A. E. M.; Jurkša, Simonas; Verlato, M.; Badoer, Simone; Pra, Stefano Dal; Mazzucato, M.; Frizziero, Eric; Bonvin, Alexandre M. J. J.

doi:10.1007/s10723-012-9246-z

Cited by 178 publications

(181 citation statements)

References 72 publications

Supporting

Mentioning

179

Contrasting

Order By: Relevance

“…The peptide sequence FFGIXLTNXLKTEEGN was built by using Maestro in an idealized α-helical form. The sequence was docked to the target protein by using the HADDOCK webserver default parameters (31,32). Chain R of the 1NVU crystal structure (21) was used, with residues L6, G15, H27, F28, V29, L56, D57, E63, Y64, R73, T74, G77, and R149 defined as the active residues.…”

Section: Kras Protein Purificationmentioning

confidence: 99%

Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices

Leshchiner

Parkhitko²,

Bird

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

145

121

View full text Add to dashboard Cite

Activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) underlie the pathogenesis and chemoresistance of ∼30% of all human tumors, yet the development of high-affinity inhibitors that target the broad range of KRAS mutants remains a formidable challenge. Here, we report the development and validation of stabilized alpha helices of son of sevenless 1 (SAH-SOS1) as prototype therapeutics that directly inhibit wild-type and mutant forms of KRAS. SAH-SOS1 peptides bound in a sequence-specific manner to KRAS and its mutants, and dose-responsively blocked nucleotide association. Importantly, this functional binding activity correlated with SAH-SOS1 cytotoxicity in cancer cells expressing wild-type or mutant forms of KRAS. The mechanism of action of SAH-SOS1 peptides was demonstrated by sequencespecific down-regulation of the ERK-MAP kinase phosphosignaling cascade in KRAS-driven cancer cells and in a Drosophila melanogaster model of Ras85D V12 activation. These studies provide evidence for the potential utility of SAH-SOS1 peptides in neutralizing oncogenic KRAS in human cancer.R AS signaling is a critical control point for a host of cellular functions ranging from cellular survival and proliferation to cellular endocytosis and motility (1). The on or off state of RAS is dictated by nucleotide exchange. GTP-bound RAS is the activated form that engages its downstream effectors with high avidity. The endogenous GTPase activity of RAS hydrolyzes GTP to GDP and inactivates signaling. This biochemical process is further regulated by GTPase-activating proteins (GAPs) that impair RAS signaling through increasing endogenous GTPase activity and guanine-nucleotide exchange factors (GEFs) that enhance RAS signaling by facilitating GDP release and, thus, GTP association. Given the central roles of RAS in cellular growth and metabolism, it is not surprising that cancer cells usurp its prosurvival activities to achieve immortality.Activating mutations in KRAS represent the most frequent oncogenic driving force among the RAS homologs K-, N-, and H-RAS, and are associated with poor prognosis and chemoresistance (2). KRAS mutations are present in ∼30% of human tumors and at even higher frequencies in cancers of the pancreas, lung, thyroid gland, colon, and liver. For example, in pancreatic ductal adenocarcinomas (PDAC) that carry a 5-y survival rate of less than 5%, activating KRAS mutations are present in more than 90% of tumors (3). Thus, therapeutic inhibition of RAS is among the highest priority goals of the cancer field. Because oncogenic forms of KRAS typically harbor single-point mutants that stabilize its active GTP-bound form, a host of recent small molecule and peptide development efforts have been aimed at disarming this pathologic biochemical state. The extremely high affinity of KRAS for its GTP substrate has hampered the development of competitive GTP inhibitors. However, a GDP mimetic that covalently modifies the mutant cysteine of KRAS G12C represents a promising approach to plugging the nucleotid...

show abstract

Section: Kras Protein Purificationmentioning

confidence: 99%

Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices

Leshchiner

Parkhitko²,

Bird

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

145

121

View full text Add to dashboard Cite

show abstract

“…Community portals, such as WeNMR [17], GriF [18], Galaxy 1 , the Extreme Science and Engineering Discovery Environment (XSEDE) 2 or the gateway to nanotechnology online simulation tools nanoHUB.org 3 have developed customised solutions for their user communities. Current efforts in Europe like SCI-BUS 4 are defining a flexible framework for developing science gateways based on the gUSE/WS-PGRADE [19] portal family.…”

Section: A State Of the Artmentioning

confidence: 99%

Supporting biodiversity studies with the EUBrazilOpenBio Hybrid Data Infrastructure

Amaral

Badía

Blanquer

et al. 2014

Concurrency and Computation

View full text Add to dashboard Cite

Abstract-EUBrazilOpenBio is a collaborative initiative addressing strategic barriers in biodiversity research by integrating open access data and user-friendly tools widely available in Brazil and Europe. The project deploys the EU-Brazil Hybrid Data Infrastructure that allows the sharing of hardware, software and data on-demand. This infrastructure provides access to several integrated services and resources to seamlessly aggregate taxonomic, biodiversity and climate data, used by processing services implementing checklist cross-mapping and ecological niche modelling. A Virtual Research Environment was created to provide users with a single entry point to processing and data resources. This article describes the architecture, demonstration use cases and experimental results.

show abstract

“…The concept of the CASD-NMR initiative was designed in 2008-2009, as part of the activities of the e-NMR/WeNMR electronic infrastructure (Wassenaar et al 2012), funded by the European Commission through grants 213010 and 261572. CASD-NMR aimed to contribute to advance the methodological development in the field, with the overarching goal to foster the adoption of automated methods throughout the biomolecular NMR community by demonstrating their reliability and the high quality of their results.…”

mentioning

confidence: 99%