9 research outputs found
Gender Specificity of Body Adiposity and Circulating Adiponectin, Visfatin, Insulin, and Insulin Growth Factor-I at Term Birth: Relation to Prenatal Growth
Abdominal Fat Partitioning and High-Molecular-Weight Adiponectin in Short Children Born Small for Gestational Age
Water Sculpts the Distinctive Shapes and Dynamics of the Tumor-Associated Carbohydrate Tn Antigens: Implications for Their Molecular Recognition
The
tumor-associated carbohydrate Tn antigens include two variants,
αGalNAc-<i>O</i>-Thr and αGalNAc-<i>O</i>-Ser. In solution, they exhibit dissimilar shapes and dynamics and
bind differently to the same protein receptor. Here, we demonstrate
experimentally and theoretically that their conformational preferences
in the gas phase are highly similar, revealing the essential role
of water. We propose that water molecules prompt the rotation around
the glycosidic linkage in the threonine derivative, shielding its
hydrophobic methyl group and allowing an optimal solvation of the
polar region of the antigen. The unusual arrangement of αGalNAc-<i>O</i>-Thr features a water molecule bound into a “pocket”
between the sugar and the threonine. This mechanism is supported by
trapping, for the first time, such localized water in the crystal
structures of an antibody bound to two glycopeptides that comprise
fluorinated Tn antigens in their structure. According to several reported
X-ray structures, installing oxygenated amino acids in specific regions
of the receptor capable of displacing the bridging water molecule
to the bulk-solvent may facilitate the molecular recognition of the
Tn antigen with threonine. Overall, our data also explain how water
fine-tunes the 3D structure features of similar molecules, which in
turn are behind their distinct biological activities
The Use of Fluoroproline in MUC1 Antigen Enables Efficient Detection of Antibodies in Patients with Prostate Cancer
A structure-based
design of a new generation of tumor-associated glycopeptides with
improved affinity against two anti-MUC1 antibodies is described. These
unique antigens feature a fluorinated proline residue, such as a (4<i>S</i>)-4-fluoro-l-proline or 4,4-difluoro-l-proline, at
the most immunogenic domain. Binding assays using biolayer interferometry
reveal 3-fold to 10-fold affinity improvement with respect to the
natural (glyco)peptides. According to X-ray crystallography and MD
simulations, the fluorinated residues stabilize the antigen–antibody
complex by enhancing key CH/π interactions. Interestingly, a
notable improvement in detection of cancer-associated anti-MUC1 antibodies
from serum of patients with prostate cancer is achieved with the non-natural
antigens, which proves that these derivatives can be considered better
diagnostic tools than the natural antigen for prostate cancer