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There is a pressing need for new molecular tools to target protein surfaces with high affinity and specificity. Here, we describe cyclic messenger RNA display with a trillion-member covalent peptide macrocycle library. Using this library, we have designed a number of high-affinity, redox-insensitive, cyclic peptides that target the signaling protein G alpha i1. In addition to cyclization, our library construction took advantage of an expanded genetic code, utilizing nonsense suppression to insert N-methylphenylalanine as a 21st amino acid. The designed macrocycles exhibit several intriguing features. First, the core motif seen in all of the selected variants is the same and shares an identical context with respect to the macrocyclic scaffold, consistent with the idea that selection simultaneously optimizes both the cyclization chemistry and the structural placement of the binding epitope. Second, detailed characterization of one molecule, cyclic G alpha i binding peptide (cycGiBP), demonstrates substantially enhanced proteolytic stability relative to that of the parent linear molecule. Third and perhaps most important, the cycGiBP peptide binds the target with very high affinity ( K i approximately 2.1 nM), similar to those of many of the best monoclonal antibodies and higher than that of the betagamma heterodimer, an endogenous G alpha i1 ligand. Overall the work provides a general route to design novel, low-molecular-weight, high-affinity ligands that target protein surfaces.
ACS Chem Biol 2007 Sep 21
PMID:Design of cyclic peptides that bind protein surfaces with antibody-like affinity. 1789 40

While many research programs have focused on the challenge of developing small molecules that can inhibit protein-protein interactions, some researchers have taken the problem one step further by attempting to develop small molecules that mimic the essential features of an entire protein. An area of particular interest has been in the field of artificial transcription factors (ATFs), where the essential function of some transcription factors is to recruit and promote the assembly of a larger transcription complex, leading to the expression of a gene of interest. The goal of synthesizing small-molecule ATFs holds promise as a means to independently control the expression of genes such as those that are misregulated in cancer and disease.
ACS Chem Biol 2007 Sep 21
PMID:The new biomimetic chemistry: artificial transcription factors. 1789 42

The machinery responsible for bacterial cell wall synthesis has proven to be an invaluable antibiotic target. Nearly 80 years after the discovery of penicillin, some of the mysteries surrounding this process are finally being unraveled.
ACS Chem Biol 2007 Sep 21
PMID:Cutting and stitching: the cross-linking of peptidoglycan in the assembly of the bacterial cell wall. 1789 43

LeuT is a bacterial amino acid transporter belonging to a large family of membrane proteins, including the neurotransmitter transporters that are targets for antidepressant drugs. The high-resolution structure of LeuT has provided an important model for understanding structure and function in this family. Two recent papers found that LeuT can bind tricyclic antidepressants, raising the possibility that it may also serve as a model for the pharmacological properties of neurotransmitter transporters.
ACS Chem Biol 2007 Sep 21
PMID:What is an antidepressant binding site doing in a bacterial transporter? 1789 44

In all kingdoms of life, RNAs undergo specific post-transcriptional modifications. More than 100 different analogues of the four standard RNA nucleosides have been identified. Modifications in ribosomal RNAs (rRNAs) are highly prevalent and cluster in regions of the ribosome that have functional importance, have a high level of nucleotide conservation, and typically lack proteins. Modifications also play roles in determining antibiotic resistance or sensitivity. A wide spectrum of chemical diversity from the modifications provides the ribosome with a broader range of possible interactions between rRNA regions, transfer RNA, messenger RNA, proteins, or ligands by influencing local rRNA folds and fine-tuning the translation process. The collective importance of the modified nucleosides in ribosome function has been demonstrated for a number of organisms, and further studies may reveal how the individual players regulate these functions through synergistic or cooperative effects.
ACS Chem Biol 2007 Sep 21
PMID:Expanding the nucleotide repertoire of the ribosome with post-transcriptional modifications. 1789 45

Ethylene performs an important function in plant growth and development. 1-aminocyclopropane-1-carboxylate (ACC) synthase (ACS), the key enzyme involved in ethylene biosynthesis, has been the focus of most ethylene studies. Here, a cotton ACS gene referred to as Gossypium hirsutum ACS1 (GhACS1), was isolated. The full-length cDNA of GhACS1 encodes for a 476-amino acid protein which harbors seven conserved regions, 11 invariant amino acid residues, and the PLP binding active site, all of which characterize ACC synthases. Alignment analysis showed that GhACS1 shared a high degree of identity with other known ACC synthases from different species. Two introns were detected in the genomic DNA sequence, and the results of Southern blot analysis suggested that there might be a multi-gene family encoding for ACC synthase in cotton. From the phylogenetic tree constructed with 24 different kinds of ACC synthases, we determined that GhACS1 falls into group II, and was closely associated with the wound-inducible ACS of citrus. The analysis of the 5' flanking region of GhACS1 revealed a group of putative cis-acting elements. The results of expression analysis showed that GhACS1 displayed its transient expression nature after wounding, abscisic acid (ABA), and CuCl(2) treatments. These results indicate that GhACS1, which was transiently expressed in response to certain stimuli, may be involved in the production of ethylene for the transmission of stress signals.
J Biochem Mol Biol 2007 Sep 30
PMID:Molecular characterization of a transient expression gene encoding for 1-aminocyclopropane-1-carboxylate synthase in cotton (Gossypium hirsutum L.). 1792 14

As chemokines are considered instrumental in thrombotic plaque rupture and erosion as well as in ischemia-reperfusion injury processes, we aimed to identify previously unknown chemokines associated with acute coronary syndromes. Plasma of 44 patients with acute myocardial infarction (AMI) and 22 controls were profiled for a panel of chemokines by multiplex analysis. Levels of CCL3 were prospectively verified in 54 patients with unstable angina pectoris (UAP). An AMI mouse model was used to assess the relationship between differentially expressed chemokines and myocardial ischemia. CCL3 levels were significantly elevated in AMI vs. controls (P=0.02) albeit, that adjustment for confounding factors attenuated this association. In support of a direct association with cardiac ischemia CCL3 levels were also seen to be elevated in patients with UAP at baseline and significantly down-regulated after 180 days (P<0.001). Importantly, baseline upper quartile levels were strongly correlated with future acute coronary syndromes (Likelihood Ratio 11.5; P<0.01). Furthermore circulating levels of CCL3 were significantly enhanced after AMI in mice (P=0.02), while CCR5(+) T-cell numbers were increased as well, suggestive of CCL3 driven T-cell homing towards the ischemic area. CCL3 levels are elevated during ACS and released upon ischemia. Since CCL3 specifically predicts future cardiovascular events, it may serve as a predictive biomarker.
J Mol Cell Cardiol 2008 Sep
PMID:CCL3 (MIP-1 alpha) levels are elevated during acute coronary syndromes and show strong prognostic power for future ischemic events. 1861 72

Heterotrimeric G-protein-coupled receptors (GPCRs) represent a large protein family responsible for mediating extracellular to intracellular signaling within a broad range of physiological contexts. Various conventional models have been used to describe their interactions with ligands and G-proteins. In recent years, however, numerous novel ligand-receptor interactions not adequately addressed by classical receptor theory have been recognized. In addition to traditional orthosteric ligands, many GPCRs can bind allosteric ligands that modulate receptor activity by interacting with distinct or overlapping receptor sites. Such ligands include positive allosteric modulators, which have become the focus of pharmaceutical drug discovery programs and have gained the attention of a growing body of basic and translational researchers within the academic community. Here, we review the fundamental aspects of allosteric GPCR modulation by small-molecule ligands, with particular focus on the emerging position of positive allosteric modulators in modern drug discovery.
ACS Chem Biol 2008 Sep 19
PMID:G-protein-coupled receptors: from classical modes of modulation to allosteric mechanisms. 1865 71

The alpha subunit of the replicative DNA polymerase III of Escherichia coli is the active polymerase of the 10-subunit bacterial replicase. The C-terminal region of the alpha subunit is predicted to contain an oligonucleotide binding (OB-fold) domain. In a series of optical tweezers experiments, the alpha subunit is shown to have an affinity for both double- and single-stranded DNA, in distinct subdomains of the protein. The portion of the protein that binds to double-stranded DNA stabilizes the DNA helix, because protein binding must be at least partially disrupted with increasing force to melt DNA. Upon relaxation, the DNA fails to fully reanneal, because bound protein interferes with the reformation of the double helix. In addition, the single-stranded DNA binding component appears to be passive, as the protein does not facilitate melting but instead binds to single-stranded regions already separated by force. From DNA stretching measurements we determine equilibrium association constants for the binding of alpha and several fragments to dsDNA and ssDNA. The results demonstrate that ssDNA binding is localized to the C-terminal region that contains the OB-fold domain, while a tandem helix-hairpin-helix (HhH) 2 motif contributes significantly to dsDNA binding.
ACS Chem Biol 2008 Sep 19
PMID:Distinct double- and single-stranded DNA binding of E. coli replicative DNA polymerase III alpha subunit. 1865 72

The antibiotic andrimid, a nanomolar inhibitor of bacterial acetyl coenzyme A carboxylase, is generated on an unusual polyketide/nonribosomal peptide enzyme assembly line in that all thiolation (T) domains/small-molecule building stations are on separate proteins. In addition, a transglutaminase homologue is used to condense andrimid building blocks together on the andrimid assembly line. The first two modules of the andrimid assembly line yields an octatrienoyl-beta-Phe-thioester tethered to the AdmI T domain, with amide bond formation carried out by a free-standing transglutaminase homologue AdmF. Analysis of the aminomutase AdmH reveals its specific conversion from l-Phe to (S)-beta-Phe, which in turn is activated by AdmJ and ATP to form (S)-beta-Phe-aminoacyl-AMP. AdmJ then transfers the (S)-beta-Phe moiety to one of the free-standing T domains, AdmI, but not AdmA, which instead gets loaded with an octatrienoyl group by other enzymes. AdmF, the amide synthase, will accept a variety of acyl groups in place of the octatrienoyl donor if presented on either AdmA or AdmI. AdmF will also use either stereoisomer of phenylalanine or beta-Phe when presented on AdmA and AdmI, but not when placed on noncognate T domains. Further, we show the polyketide synthase proteins responsible for the polyunsaturated acyl cap can be bypassed in vitro with N-acetylcysteamine as a low-molecular-weight acyl donor to AdmF and also in vivo in an Escherichia coli strain bearing the andrimid biosynthetic gene cluster with a knockout in admA.
ACS Chem Biol 2008 Sep 19
PMID:Gatekeeping versus promiscuity in the early stages of the andrimid biosynthetic assembly line. 1865 73


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