Scaffolds for Blocking Protein-Protein Interactions

Hershberger, Stefan J.; Lee, Song-Gil; Chmielewski, Jean

doi:10.2174/156802607780906726

Cited by 59 publications

(40 citation statements)

References 105 publications

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“…A possible strategy for anticancer drugs is therefore the development or identification of small-molecule compounds that are able to disrupt the eIF4F complex (40). Targeting protein-protein interactions with small molecules is usually difficult because of the large size and flatness of the surfaces involved and because most of the surface residues usually are not essential for binding (41,42). However, eIF4G's Trp-579 interaction with the complementary pocket on the eIF4A surface could result in an efficient target for small molecules.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of the yeast eIF4A-eIF4G complex: An RNA-helicase controlled by protein–protein interactions

Schutz

Bumann

Oberholzer

et al. 2008

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

226

324

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Translation initiation factors eIF4A and eIF4G form, together with the cap-binding factor eIF4E, the eIF4F complex, which is crucial for recruiting the small ribosomal subunit to the mRNA 5 end and for subsequent scanning and searching for the start codon. eIF4A is an ATP-dependent RNA helicase whose activity is stimulated by binding to eIF4G. We report here the structure of the complex formed by yeast eIF4G's middle domain and full-length eIF4A at 2.6-Å resolution. eIF4A shows an extended conformation where eIF4G holds its crucial DEAD-box sequence motifs in a productive conformation, thus explaining the stimulation of eIF4A's activity. A hitherto undescribed interaction involves the amino acid Trp-579 of eIF4G. Mutation to alanine results in decreased binding to eIF4A and a temperature-sensitive phenotype of yeast cells that carry a Trp579Ala mutation as its sole source for eIF4G. Conformational changes between eIF4A's closed and open state provide a model for its RNA-helicase activity.translation initiation ͉ DEAD-box protein ͉ X-ray structure ͉ eIF4F T ranslation initiation in eukarya is usually the rate-limiting and most tightly controlled stage of polypeptide synthesis (reviewed in refs. 1-3). For the majority of eukaryotic mRNAs, the cap-dependent pathway is used for translation initiation (3). It comprises four consecutive steps: (i) formation of the 43S preinitiation complex consisting of the 40S ribosomal subunit, initiation factors (eIF2, eIF3), and Met-tRNA i ; (ii) recruitment of the 43S preinitiation complex to the capped 5Ј end of the mRNA; (iii) scanning of the 5Ј untranslated region of the mRNA and start codon recognition; and (iv) joining of the large 60S ribosomal subunit and assembly of the 80S ribosome.Approximately a dozen eukaryotic translation initiation factors (eIFs) are needed for this process. A central component of the second and third step is eIF4F, a heterotrimeric stable complex consisting of the cap-binding protein eIF4E, the DEAD-box helicase eIF4A, and the central multiscaffold protein eIF4G, which possesses additional binding sites for the poly(A)-binding protein PABP and, in mammalia, for eIF3 (Fig. 1A). Mammalian eIF4G possesses a second eIF4A binding site in its C-terminal region in proximity to a binding site for protein kinase Mnk1 (mitogen-activated protein kinase-interacting kinase), which phosphorylates eIF4E. Crystal structures of the central and the C-terminal region of human eIF4GII reveal the formation of one or two HEAT domains, respectively (4, 5)Saccharomyces cerevisiae possesses two genes encoding for eIF4G, TIF4631 and TIF4632. The gene products, eIF4GI and eIF4GII, are 952 and 914 aa long and share Ϸ50% sequence identity. Deletion of one of these genes is tolerated by yeast cells, but double deletion of both genes causes lethality. Interaction of eIF4G with eIF4A is essential for the cell (6, 7). The 45-kDa initiation factor 4A (eIF4A) is a prototypical DEAD-box helicase (8). Its ATPase activity is RNA-dependent and its activity is substantially enhanced in ...

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Section: Discussionmentioning

confidence: 99%

Crystal structure of the yeast eIF4A-eIF4G complex: An RNA-helicase controlled by protein–protein interactions

Schutz

Bumann

Oberholzer

et al. 2008

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

226

324

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“…It is also conceivable that these dye structures can be considered as being 'privileged structures' for protein binding in the sense of being organic templates capable of mimicking surfaces of protein-recognition motifs (e.g., a-helix mimetics) (Che et al, 2006;Fletcher and Hamilton, 2006;Hershberger et al, 2007) and, hence, being a good starting point in the search for PPIIs.…”

Section: Discussionmentioning

confidence: 99%

Organic dyes as small molecule protein–protein interaction inhibitors for the CD40–CD154 costimulatory interaction

Buchwald

Margolles-Clark

Kenyon

et al. 2009

J of Molecular Recognition

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It is becoming increasingly clear that small molecules can often act as effective protein-protein interaction (PPI) inhibitors, an area of increasing interest for its many possible therapeutic applications. We have identified several organic dyes and related small molecules that (i) concentration-dependently inhibit the important CD40-CD154 costimulatory interaction with activities in the low micromolar (microM) range, (ii) show selectivity toward this particular PPI, (iii) seem to bind on the surface of CD154, and (iv) concentration-dependently inhibit the CD154-induced B cell proliferation. They were identified through an iterative activity screening/structural similarity search procedure starting with suramin as lead, and the best smaller compounds, the main focus of the present work, achieved an almost 3-fold increase in ligand efficiency (DeltaG(0)/nonhydrogen atom = 0.8 kJ/N(nHa)) approaching the average of known promising small-molecule PPI inhibitors (approximately 1.0 kJ/N(nHa)). Since CD154 is a member of the tumor necrosis factor (TNF) superfamily of cell surface interaction molecules, inhibitory activities on the TNF-R1-TNF-alpha interactions were also determined to test for specificity, and the compounds selected here all showed more than 30-fold selectivity toward the CD40-CD154 interaction. Because of their easy availability in various structural scaffolds and because of their good protein-binding ability, often explored for tissue-specific staining and other purposes, such organic dyes can provide a valuable addition to the chemical space searched to identify small molecule PPI inhibitors in general.

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“…A number of recent reviews have addressed this topic. [130][131][132] Suggesting important role of TM interactions that mediate ligand-induced SR dimerization (oligomerization) and homo-interactions between CYTO domains that result in formation of competent signaling oligomers (Fig. 5A), the SCHOOL model of SR signaling reveals these interactions as important points for intervention to modulate SR signaling.…”

Section: Multichainmentioning

confidence: 99%

The SCHOOL of nature: II. Protein order, disorder, and oligomericity in transmembrane signaling

Sigalov¹

2010

Self/Nonself

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Scaffolds for Blocking Protein-Protein Interactions

Cited by 59 publications

References 105 publications

Crystal structure of the yeast eIF4A-eIF4G complex: An RNA-helicase controlled by protein–protein interactions

Crystal structure of the yeast eIF4A-eIF4G complex: An RNA-helicase controlled by protein–protein interactions

Organic dyes as small molecule protein–protein interaction inhibitors for the CD40–CD154 costimulatory interaction

The SCHOOL of nature: II. Protein order, disorder, and oligomericity in transmembrane signaling

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