32 research outputs found
Conserved structure of genes encoding components of botulinum neurotoxin complex M and the sequence of the gene coding for the nontoxic component in nonproteolyticClostridium botulinum type F
Analysis of interactions in a tapasin/class I complex provides a mechanism for peptide selection
We examined interactions in a soluble tapasin (TPN)/HLA-B(*)0801 complex to gain mechanistic insights into the functions of TPN. Results show that TPN acts as a chaperone by increasing the ratio of active-to-inactive peptide-deficient HLA-B(*)0801 molecules in solution. TPN causes peptides to associate and dissociate faster owing to its effect on widening the binding groove of HLA-B(*)0801 molecules. Our data indicate that a TPN-assisted mechanism of peptide selection relies on disruption of conserved hydrogen bonds at the C-terminal end of the groove. Peptide sequence-dependent interactions along the entire length of the groove also play a role in this mechanism. We suggest that TPN influences presentation of antigenic peptides according to a mechanistically complicated process in which bound candidate peptides that are unable to conformationally disengage TPN from class I molecules are excluded from the repertoire. Overall, these studies unify our understanding of the functions of TPN
Tracking Molecular Recognition at the Atomic Level with a New Protein Scaffold Based on the OB-Fold
Protein interactomes of protein phosphatase 2A B55 regulatory subunits reveal B55-mediated regulation of replication protein A under replication stress
A comprehensive analysis of the thermodynamic events involved in ligand–receptor binding using CoRIA and its variants
Quantitative Structure-Activity Relationships(QSAR) are being used since decades for prediction of biological activity, lead optimization, classification, identification and explanation of the mechanisms of drug action, and prediction of novel structural leads in drug discovery. Though the technique has lived up to its expectations in many aspects, much work still needs to be done in relation to problems related to the rational design of peptides. Peptides are the drugs of choice in many situations, however, designing them rationally is a complicated task and the complexity increases with the length of their sequence. In order to deal with the problem of peptide optimization, one of our recently developed QSAR formalisms CoRIA (Comparative Residue Interaction Analysis) is being expanded and modified as: reverse-CoRIA (rCoRIA) and mixed- CoRIA (mCoRIA) approaches. In these methodologies, the peptide is fragmented into individual units and the interaction energies (van der Waals, Coulombic and hydrophobic) of each amino acid in the peptide with the receptor as a whole(rCoRIA) and with individual active site residues in the receptor (mCoRIA) are calculated, which along with other thermodynamic descriptors, are used as independent variables that are correlated to the biological activity by chemometric methods. As a test case, the three CoRIA methodologies have been validated on a dataset of diverse nonamer peptides that bind to the Class I major histocompatibility complex molecule HLA-A*0201, and for which some structure activity relationships have already been reported. The different models developed, and validated both internally as well as externally, were found to be robust with statistically significant values of r2 (correlation coefficient)and r2 pred (predictive r2). These models were able to identify all the structure activity relationships known for this class of peptides, as well uncover some new relationships. This means that these methodologies will perform well for other peptide datasets too. The major advantage of these approaches is that they explicitly utilize the 3D structures of small molecules or peptides as well as their macromolecular targets, to extract position-specific information about important interactions between the ligand and receptor, which can assist the medicinal and computational chemists in designing new molecules, and biologists in studying the influence of mutations in the target receptor on ligand binding
Is being conservative at home whilst taking risks abroad a suitable competitive strategy? The case of Spanish Family Firms internationalizing to Mexico
Family firms’ (FFs) importance for industrialized and developing countries and the growing competition has led to an increased interest in knowing how FFs develop their competitive strategies. Since FFs usually have a long-term vision when deciding how to compete, analyzing competitive strategies –usually linked with the long-term– makes even more sense. Furthermore, FFs’ behavior is especially interesting when they have been internationalized. Thus, the purpose of our study is to improve the understanding of the competitive strategies of FFs’ internationalizing to Mexico, namely exploitation (at a national level) and exploration (at international level). Briefly, a firm’s exploitation strategy is characterized by better-using firms’ existing resources and knowledge, whereas a firm’s exploration strategy involves exploring new ways of doing. Based on data collected from 81 CEOs of Spanish firms that have been internationalized to Mexico, we use partial least squares structural equation modeling (PLS-SEM) technique. We conclude that FFs’ exploitation strategy (at a national level) has a positive impact on firms’ exploration strategy (at international level). In other words, being more efficient and leveraging current knowledge at a national level helps to pursue opportunities internationally actively