67 research outputs found
Structural characterization of a protein adsorbed on aluminum hydroxide adjuvant in vaccine formulation
SARS-CoV-2 Mproinhibition by a zinc ion: structural features and hints for drug design
The first structure of the SARS-CoV-2 main protease in complex with an isolated zinc ion provides solid ground for the design of potent and selective metal-conjugated inhibitors
Molecular Insights into O-Linked Sialoglycans Recognition by the Siglec-Like SLBR-N (SLBRUB10712) of Streptococcus gordonii
The catalytic domain of MMP-1 studied through tagged lanthanides
AbstractPseudocontact shifts (pcs) and paramagnetic residual dipolar couplings (rdc) provide structural information that can be used to assess the adequacy of a crystallographic structure to represent the solution structure of a protein. This can be done by attaching a lanthanide binding tag to the protein. There are cases in which only local rearrangements are sufficient to match the NMR data and cases where significant secondary structure or domain rearrangements from the solid state to the solution state are needed. We show that the two cases are easily distinguishable. Whereas the use of solution restraints in the latter case is described in the literature, here we deal with how to obtain a better model of the solution structure in a case (the catalytic domain of the matrix metalloproteinase MMP-1) of the former class
Engineering l-asparaginase for spontaneous formation of calcium phosphate bioinspired microreactors.
NMR quality control of fragment libraries for screening
Fragment-based screening has evolved as a remarkable approach within the drug discovery process both in the industry and academia. Fragment screening has become a more structure-based approach to inhibitor development, but also towards development of pathway-specific clinical probes. However, it is often witnessed that the availability, immediate and long-term, of a high quality fragment-screening library is still beyond the reach of most academic laboratories. Within iNEXT (Infrastructure for NMR, EM and X-rays for Translational research), a EU-funded Horizon 2020 program, a collection of 782 fragments were assembled utilizing the concept of "poised fragments" with the aim to facilitate downstream synthesis of ligands with high affinity by fragment ligation. Herein, we describe the analytical procedure to assess the quality of this purchased and assembled fragment library by NMR spectroscopy. This quality assessment requires buffer solubility screening, comparison with LC/MS quality control and is supported by state-of-the-art software for high throughput data acquisition and on-the-fly data analysis. Results from the analysis of the library are presented as a prototype of fragment progression through the quality control process
A Structurally Simple Vaccine Candidate Reduces Progression and Dissemination of Triple-Negative Breast Cancer
The Tn antigen is a well-known tumor-associated carbohydrate determinant, often incorporated in glycopeptides to develop cancer vaccines. Herein, four copies of a conformationally constrained mimetic of the antigen TnThr (GalNAc-Thr) were conjugated to the adjuvant CRM197, a protein licensed for human use. The resulting vaccine candidate, mime[4]CRM elicited a robust immune response in a triple-negative breast cancer mouse model, correlated with high frequency of CD4+ T cells and low frequency of M2-type macrophages, which reduces tumor progression and lung metastasis growth. Mime[4]CRM-mediated activation of human dendritic cells is reported, and the proliferation of mime[4]CRM-specific T cells, in cancer tissue and peripheral blood of patients with breast cancer, is demonstrated. The locked conformation of the TnThr mimetic and a proper presentation on the surface of CRM197 may explain the binding of the conjugate to the anti-Tn antibody Tn218 and its efficacy to fight cancer cells in mice
Mixing Aβ(1-40) and Aβ(1-42) peptides generates unique amyloid fibrils
Recent structural studies show distinct morphologies for the fibrilsof Ab(1-42) and Ab(1-40), which are believed not to co-fibrillize.We describe here a novel, structurally-uniform 1 : 1 mixed fibrillarspecies, which differs from bothpure fibrils. It forms preferen-tially even when Ab(1-42) : Ab(1-40) peptides are mixed in a non-stoichiometric ratio
- …