Twist and shout: Coiled‐coil forming α‐helices are of great significance in understanding tertiary structural formation (the figure shows GCN4; an example of a parallel dimeric coiled coil), the design of new proteins, and the control of the oligomeric state. The apparent simplicity of coiled coils is misleading, and rules governing such features are far from fully established. Requirements for the specific pairings of helices during coiled‐coil formation are discussed, as are the peculiarities within such domains that give proteins their unique function. By taking advantage of our increasing understanding of this structural class, a growing number of biological and therapeutic applications are being sought.

Finally, and with wider implications, we have compiled a method for predicting interaction of parallel, dimeric coiled coils, using our T m data as a training set, and applying it to 59 bZIP proteins previously reported. Our algorithm, unlike others to date, accounts for helix propensity, which is found to be integral in coiled coil stability. Indeed, in applying the algorithm to these 59 2 bZIP interactions, we were able to correctly identify 92% of all strong interactions and 92% of all noninteracting pairs.bioinformatics ͉ protein design ͉ protein stability ͉ protein-protein interaction ͉ dominant negative T he dimeric transcription factor activator protein-1 (AP-1) comprises Jun, Fos, activating transcription factor, and musculoaponeurotic fibrosarcoma families. Chief mammalian cell AP-1 constituents, Jun and Fos, contain a transactivation domain, a basic region for recognizing a DNA consensus sequence and a leucine zipper [coiled coil (CC)] region (see Fig. 1). The latter, in dimerizing, permits the two basic domains to bind to their consensus sequence. Such transcription factors, known as basic-zipper or bZIP proteins, are found at the closing stages of mitogen-activated protein kinase signaling cascades (e.g., the RAS pathway). AP-1 is implicated in various cancers where it can become up-regulated or overexpressed (1), and has been shown to be important in cell growth initiation, with c-Jun and c-Fos identified as cellular counterparts to viral oncoproteins v-Jun and v-Fos, thus establishing their role in tumorigenesis (2). Indeed, they are central in numerous oncogenic pathways and could therefore be prime candidates in anticancer drug design. However, AP-1 can also have antiproliferative properties, depending on subunit composition, transcription level, posttranslational modification (e.g., phosphorylation), and interaction with other proteins (e.g., Jun N-terminal kinase); this is manifested by the preponderance of different AP-1 family members in different types of tissue cancer. . Alternative residue options were included at e and g positions, and were aimed at varying electrostatic attraction levels at the dimeric interface. Other alternative residues, largely taken from homologues (see key), were introduced to the library pool at the solvent exposed b, c, and f positions. Wild-type residues removed from libraries are struck through in green, newly introduced amino acids are marked red, and wildtype positions left in the library are marked blue. Library winner selections are circled green. Position c1 E (marked red) is for additional N-cap stability, whereas b3 Y assists with concentration determination. Capping motifs have also been added.

Alpha-synuclein (αS) is the major constituent of Lewy bodies and a pathogenic hallmark of all synucleinopathathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). All diseases are determined by αS aggregate deposition but can be separated into distinct pathological phenotypes and diagnostic criteria. Here we attempt to reinterpret the literature, particularly in terms of how αS structure may relate to pathology. We do so in the context of a rapidly evolving field, taking into account newly revealed structural information on both native and pathogenic forms of the αS protein, including recent solid state NMR and cryoEM fibril structures. We discuss how these new findings impact on current understanding of αS and PD, and where this information may direct the field.

Abstractc-Myc is a transcription factor that is constitutively and aberrantly expressed in over 70% of human cancers. Its direct inhibition has been shown to trigger rapid tumor regression in mice with only mild and fully reversible side effects, suggesting this to be a viable therapeutic strategy. Here we reassess the challenges of directly targeting c-Myc, evaluate lessons learned from current inhibitors, and explore how future strategies such as miniaturisation of Omomyc and targeting E-box binding could facilitate translation of c-Myc inhibitors into the clinic.

The key pathogenic event in the onset of Alzheimer's disease (AD) is believed to be the aggregation of the beta-amyloid (Abeta) peptide into toxic oligomers. Molecules that interfere with this process may therefore act as therapeutic agents for the treatment of AD. N-Methylated peptides (meptides) are a general class of peptide aggregation inhibitors that act by binding to one face of the aggregating peptide but are unable to hydrogen bond on the other face, because of the N-methyl group replacing a backbone NH group. Here, we optimize the structure of meptide inhibitors of Abeta aggregation, starting with the KLVFF sequence that is known to bind to Abeta. We varied the meptide length, N-methylation sites, acetylation, and amidation of the N and C termini, side-chain identity, and chirality, via five compound libraries. Inhibitor activity was tested by thioflavin T binding, affinity chromatography, electron microscopy, and an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide toxicity assay. We found that inhibitors should have all d chirality, have a free N terminus but an amidated C terminus, and have large, branched hydrophobic side chains at positions 1-4, while the side chain at position 5 was less important. A single N-methyl group was necessary and sufficient. The most active compound, d-[(chGly)-(Tyr)-(chGly)-(chGly)-(mLeu)]-NH(2), was more active than all previously reported peptide inhibitors. Its related non-N-methylated analogues were insoluble and toxic.

Biochemistry Biochemistry Z 0250 Coiled Coil Domains: Stability, Specificity, and Biological Implications -[77 refs.]. -(MASON, J. M.; ARNDT*, K. M.; ChemBioChem 5 (2004) 2, 170-176; Inst. Biol. II, Microbiol., Albert-Ludwigs-Univ., D-79104 Freiburg/Br., Germany; Eng.) -Lindner 15-270

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The concept of peptides as therapeutic agents has been historically disregarded by the pharmaceutical industry on account of their susceptibility to degradation, their size and consequent limitations in methods of delivery. Recently, however, there has been a surge of interest in peptides and their mimetics as potential antagonists for therapeutic intervention. This is in part due to the increased half-life and oral availability that has been achieved for a number of peptide-based systems, the introduction and acceptance of alternative delivery methods, and the prevalence of proteomics to identify countless protein-protein interaction targets. The use of peptides and molecules that mimic their function therefore has great potential to effectively target a range of proteins that are pathogenically implicated in numerous diseases.