Targeting protein–protein interactions, a wide open field for drug design

AbstractTargeting protein–protein interactions has long been considered as a very difficult if impossible task, but over the past decade, front lines have moved. The number of successful examples is exponentially growing. This review presents a rapid overview of recent advances in this field considering the strengths and weaknesses of the small molecule approaches and alternative strategies such as the selection or design of artificial antibodies, peptides or peptidomimetics

The ALADIN Interactive Sky Atlas

The Aladin interactive sky atlas, developed at CDS, is a service providing simultaneous access to digitized images of the sky, astronomical catalogues, and databases. The driving motivation is to facilitate direct, visual comparison of observational data at any wavelength with images of the optical sky, and with reference catalogues. The set of available sky images consists of the STScI Digitized Sky Surveys, completed with high resolution images of crowded regions scanned at the MAMA facility in Paris. A Java WWW interface to the system is available at: http://aladin.u-strasbg.fr/Comment: 8 pages, 3 Postscript figures; to be published in A&

The SIMBAD astronomical database

Simbad is the reference database for identification and bibliography of astronomical objects. It contains identifications, `basic data', bibliography, and selected observational measurements for several million astronomical objects. Simbad is developed and maintained by CDS, Strasbourg. Building the database contents is achieved with the help of several contributing institutes. Scanning the bibliography is the result of the collaboration of CDS with bibliographers in Observatoire de Paris (DASGAL), Institut d'Astrophysique de Paris, and Observatoire de Bordeaux. When selecting catalogues and tables for inclusion, priority is given to optimal multi-wavelength coverage of the database, and to support of research developments linked to large projects. In parallel, the systematic scanning of the bibliography reflects the diversity and general trends of astronomical research. A WWW interface to Simbad is available at: http://simbad.u-strasbg.fr/SimbadComment: 14 pages, 5 Postscript figures; to be published in A&A

Structural and functional analysis of SGT1–HSP90 core complex required for innate immunity in plants

SGT1 (Suppressor of G2 allele of skp1), a co-chaperone of HSP90 (Heat-shock protein 90), is required for innate immunity in plants and animals. Unveiling the cross talks between SGT1 and other co-chaperones such as p23, AHA1 (Activator of HSP90 ATPase 1) or RAR1 (Required for Mla12 resistance) is an important step towards understanding the HSP90 machinery. Nuclear magnetic resonance spectroscopy and mutational analyses of HSP90 revealed the nature of its binding with the CS domain of SGT1. Although CS is structurally similar to p23, these domains were found to non-competitively bind to various regions of HSP90; yet, unexpectedly, full-length SGT1 could displace p23 from HSP90. RAR1 partly shares the same binding site with HSP90 as the CS domain, whereas AHA1 does not. This analysis allowed us to build a structural model of the HSP90–SGT1 complex and to obtain a compensatory mutant pair between both partners that is able to restore virus resistance in vivo through Rx (Resistance to potato virus X) immune sensor stabilization

Optimal anchoring of a foldamer inhibitor of ASF1 histone chaperone through backbone plasticity

Sequence-specific oligomers with predictable folding patterns, i.e., foldamers, provide new opportunities to mimic.-helical peptides and design inhibitors of protein-protein interactions. One major hurdle of this strategy is to retain the correct orientation of key side chains involved in protein surface recognition. Here, we show that the structural plasticity of a foldamer backbone may notably contribute to the required spatial adjustment for optimal interaction with the protein surface. By using oligoureas as. helix mimics, we designed a foldamer/peptide hybrid inhibitor of histone chaperone ASF1, a key regulator of chromatin dynamics. The crystal structure of its complex with ASF1 reveals a notable plasticity of the urea backbone, which adapts to the ASF1 surface to maintain the same binding interface. One additional benefit of generating ASF1 ligands with nonpeptide oligourea segments is the resistance to proteolysis in human plasma, which was highly improved compared to the cognate alpha-helical peptide

The ALADIN Interactive Sky Atlas. A reference tool for identification of astronomical sources

8 pages, 3 Postscript figuresThe Aladin interactive sky atlas, developed at CDS, is a service providing simultaneous access to digitized images of the sky, astronomical catalogues, and databases. The driving motivation is to facilitate direct, visual comparison of observational data at any wavelength with images of the optical sky, and with reference catalogues. The set of available sky images consists of the STScI Digitized Sky Surveys, completed with high resolution images of crowded regions scanned at the MAMA facility in Paris. A Java WWW interface to the system is available at: http://aladin.u-strasbg.fr

Integrating astronomical data and information services at the CDS", this conference

The CDS is providing several unique services to the world-wide astronomical community: the catalogue service, the SIMBAD database, the ALADIN project, bibliography and literature search, yellow pages, etc. We describe how the CDS works at providing a global perspective on astronomical data and information, with the help of recent technological developments.

Structural and Functional Analysis of SGT1 Reveals That Its Interaction with HSP90 Is Required for the Accumulation of Rx, an R Protein Involved in Plant Immunity[W][OA]

SGT1 (for suppressor of G2 allele of skp1) and RAR1 (for required for Mla12 resistance) are highly conserved eukaryotic proteins that interact with the molecular chaperone HSP90 (for heat shock protein90). In plants, SGT1, RAR1, and HSP90 are essential for disease resistance triggered by a number of resistance (R) proteins. Here, we present structural and functional characterization of plant SGT1 proteins. Random mutagenesis of Arabidopsis thaliana SGT1b revealed that its CS (for CHORD-SGT1) and SGS (for SGT1 specific) domains are essential for disease resistance. NMR-based interaction surface mapping and mutational analyses of the CS domain showed that the CHORD II domain of RAR1 and the N-terminal domain of HSP90 interact with opposite sides of the CS domain. Functional analysis of the CS mutations indicated that the interaction between SGT1 and HSP90 is required for the accumulation of Rx, a potato (Solanum tuberosum) R protein. Biochemical reconstitution experiments suggest that RAR1 may function to enhance the SGT1–HSP90 interaction by promoting ternary complex formation

Optimal Anchoring of a Urea-based Foldamer Inhibitor of ASF1 Histone Chaperone Through Backbone Plasticity

Sequence-specific oligomers with predictable folding patterns, i.e. foldamers provide new opportunities to mimic α-helical peptides and design inhibitors of protein-protein interactions. One major hurdle of this strategy is to retain the correct orientation of key side chains involved in protein surface recognition. Here, we show that the structural plasticity of a foldamer backbone may significantly contribute to the required spatial adjustment for optimal interaction with the protein surface. By using oligoureas as α-helix mimics, we designed a foldamer/peptide hybrid inhibitor of histone chaperone ASF1, a key regulator of chromatin dynamics. The crystal structure of its complex with ASF1 reveals a striking plasticity of the urea backbone, which adapts to the ASF1 surface to maintain the same binding interface. One additional benefit of generating ASF1 ligands with non-peptide oligourea segments is the resistance to proteolysis in human plasma which was highly improved compared to the cognate α-helical peptide. </p