6 research outputs found
Earthquake forecasting in Italy, before and after Umbria-Marche seismic sequence 1997. A review of the earthquake occurrence modeling at different spatio-temporal-magnitude scales.
The main goal of this work is to review the scientific researches carried out before and after the Umbria-Marche sequence related to the earthquake forecasting/prediction in Italy. In particular, I focus the attention on models that aim addressing three main practical questions: was (is) Umbria-Marche a region with high probability of occurrence of a destructive earthquake? Was a precursory activity recorded before the mainshock(s)? What was our capability to model the spatio-temporal-magnitude evolution of that seismic sequence? The models are reviewed pointing out what we have learned after the Umbria-Marche earthquakes, in terms of physical understanding of earthquake occurrence process, and of improving our capability to forecast earthquakes and to track in real-time seismic sequences
Structural Characterization of the Cyclic Cystine Ladder Motif of θ‑Defensins
The θ-defensins are, to date,
the only known ribosomally
synthesized cyclic peptides in mammals, and they have promising antimicrobial
bioactivities. The characteristic structural motif of the θ-defensins
is the cyclic cystine ladder, comprising a cyclic peptide backbone
and three parallel disulfide bonds. In contrast to the cyclic cystine
knot, which characterizes the plant cyclotides, the cyclic cystine
ladder has not been as well described as a structural motif. Here
we report the solution structures and nuclear magnetic resonance relaxation
properties in aqueous solution of three representative θ-defensins
from different species. Our data suggest that the θ-defensins
are more rigid and structurally defined than previously thought. In
addition, all three θ-defensins were found to self-associate
in aqueous solution in a concentration-dependent and reversible manner,
a property that might have a role in their mechanism of action. The
structural definition of the θ-defensins and the cyclic cystine
ladder will help to guide exploitation of these molecules as structural
frameworks for the design of peptide drugs
Insights into the Molecular Flexibility of θ‑Defensins by NMR Relaxation Analysis
θ-Defensins
are mammalian cyclic peptides that have antimicrobial
activity and show potential as stable scaffolds for peptide-based
drug design. The cyclic cystine ladder structural motif of θ-defensins
has been characterized using NMR spectroscopy and is important for
their structure and stability. However, the effect of the pronounced
elongated topology of θ-defensins on their molecular motion
is not yet understood. Studies of molecular motion by NMR relaxation
measurements have been facilitated by the recent development of a
semirecombinant method for producing cyclic peptides that allows for
isotopic labeling. Here we have undertaken a multifield <sup>15</sup>N NMR relaxation analysis of the anti-HIV θ-defensin, HTD-2,
and interpreted the experimental data using various models of overall
and internal molecular motion. We found that it was necessary to apply
a model that includes internal motion to account for the variations
in the experimental T<sub>1</sub> and NOE data at different backbone
amide sites in the peptide. Although an isotropic model with internal
motion was the simplest model that provided a satisfactory fit with
the experimental data, we cannot exclude the possibility that overall
motion is anisotropic, especially considering the strikingly elongated
topology of θ-defensins. The presence of flexible side chains,
self-association, interactions with solvent, and internal motions
are all potential contributors to the observed relaxation data. Internal
motion consistent with the constraints imposed by the cyclic cystine
ladder was observed in that the order parameters, <i>S</i><sup>2</sup>, show that residues in the turns are more flexible than
those in the β-sheet. This study provides insights into the
dynamics of θ-defensins and information that might be useful
in their application as scaffolds in drug design
Althusser and the Critique of Political Economy
Two disulfide-containing peptides,
barrettides A (<b>1</b>) and B (<b>2</b>), from the cold-water
marine sponge <i>Geodia barretti</i> are described. Those
31 amino acid residue
long peptides were sequenced using mass spectrometry methods and structurally
characterized using NMR spectroscopy. The structure of <b>1</b> was confirmed by total synthesis using the solid-phase peptide synthesis
approach that was developed. The two peptides were found to differ
only at a single position in their sequence. The three-dimensional
structure of <b>1</b> revealed that these peptides possess a
unique fold consisting of a long β-hairpin structure that is
cross-braced by two disulfide bonds in a ladder-like arrangement.
The peptides are amphipathic in nature with the hydrophobic and charged residues clustered on separate
faces of the molecule. The barrettides were found not to inhibit the
growth of either <i>Escherichia coli</i> or <i>Staphylococcus
aureus</i> but displayed antifouling activity against barnacle
larvae (<i>Balanus improvisus</i>) without lethal effects
in the concentrations tested
Understanding the Molecular Basis of Toxin Promiscuity: The Analgesic Sea Anemone Peptide APETx2 Interacts with Acid-Sensing Ion Channel 3 and hERG Channels via Overlapping Pharmacophores
The
sea anemone peptide APETx2 is a potent and selective blocker
of acid-sensing ion channel 3 (ASIC3). APETx2 is analgesic in a variety
of rodent pain models, but the lack of knowledge of its pharmacophore
and binding site on ASIC3 has impeded development of improved analogues.
Here we present a detailed structure–activity relationship
study of APETx2. Determination of a high-resolution structure of APETx2
combined with scanning mutagenesis revealed a cluster of aromatic
and basic residues that mediate its interaction with ASIC3. We show
that APETx2 also inhibits the off-target hERG channel by reducing
the maximal current amplitude and shifting the voltage dependence
of activation to more positive potentials. Electrophysiological screening
of selected APETx2 mutants revealed partial overlap between the surfaces
on APETx2 that mediate its interaction with ASIC3 and hERG. Characterization
of the molecular basis of these interactions is an important first
step toward the rational design of more selective APETx2 analogues
Elliott et al. (2014). Plant Cell 10.1105/tpc.114.123620 Supplemental Data
Supplemental Figures 1-24, Supplemental Tables 1-11, Supplemental Methods, Supplemental Dataset 1-