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Computer-Aided Epitope Identification and Design of Epitope Mimetics
Published in Mesut Karahan, Synthetic Peptide Vaccine Models, 2021
Short peptidic fragments, resulting from protein degradation and recognized by T lymphocytes, unavoidably lack an intrinsic structural organization. Compatible MHC proteins are required to form stable complexes with these peptides. “Stable” is the key word here, because the peptide-MHC complex subsequently needs to form a ternary complex with a T cell receptor. A weak binding between the peptide and MHC would impose too large an entropic penalty on the formation of such a ternary complex. MHC proteins therefore possess well-defined cavities, capable of accepting peptidic fragments, forming high affinity complexes with them, and assisting them in assuming stable spatial organization (Figure 17.1).
Interleukin-6 Receptor
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Stefan Rose-John, Peter C. Heinrich
The ultimate aim should be to unravel the chain of events from the interaction of IL-6 with its hepatic receptor to the transcriptional activation of acute phase protein genes in the nucleus. For the receptor as well as the ternary complex, an X-ray analysis of the various structures needs to be performed. Most obscure is the pathway of the IL-6 signal to the nucleus. It can be anticipated that several kinases involved in IL-6 signaling will be identified and characterized. Finally, the molecular mechanisms by which acute phase protein genes are switched on have to be elucidated. Different combinations of transcription factors might represent the molecular basis for the pleiotropic spectrum of action of IL-6 in different biological systems.
The Major Histocompatibility Complex
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
This is the major pathway for processing proteins imported from outside the cell. Antigens are degraded in acidic vacuoles, and peptides are then sorted according to their affinity with various HLA class II molecules. The complete ternary complex (heterodimeric class II + peptide) is then expressed on the surface for recognition by CD4+ cells (Figure 8–11). This mechanism is principally concerned with alerting the immune system to the presence of extracellular parasites, as well as organisms which replicate intracellularly within phagocytic vacuoles. There is evidence that peptides generated within the cytoplasm may also associate with MHC class II molecules. External (to the cell) self antigens are also internalized, degraded, and presented; self peptides may also be generated within the endoplasmic reticulum, or from cytosolic proteins via autophagosomes. As with class I, presentation of self is constitutive.
Kinetic analysis of ternary and binary binding modes of the bispecific antibody emicizumab
Published in mAbs, 2023
Stefanie Mak, Agnes Marszal, Nena Matscheko, Ulrich Rant
The binding properties of bsAbs are crucial for their function, as the propensity to form an interaction, the stability (half-life) of the interaction, and the equilibrium affinity, all influence the mechanism of action. For a binary interaction between two molecules, binding can be described in a straightforward manner by three biophysical parameters, namely, the association rate constant kon, the dissociation rate constant koff, and the dissociation constant in equilibrium Kd = koff/kon. For bispecific binders, the situation is more complex,8,9 as one must consider two different binary interactions giving rise to a ternary interaction (Figure 1). Moreover, the ternary complex may be stabilized or destabilized by other cooperativity factors, such as the steric alignment of the three binders, conformational flexibility, or the local concentrations of molecular moieties participating in the interaction.4,10–13
Models of enzyme inhibition and apparent dissociation constants from kinetic analysis to study the differential inhibition of aldose reductase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Francesco Balestri, Mario Cappiello, Roberta Moschini, Umberto Mura, Antonella Del-Corso
It is evident that this approach fails in giving a rationale for the inhibition data reported above (Figure 1), in which appKM/appVmax versus [I] decreases. appKM can either increase or decrease with, at maximum, the same steepness of appVmax. If we (at the moment) rule out that the inhibitor may induce an increase in the affinity of the enzyme for the substrate, the explanation of a negative slope of the appKM/appVmax = f ([I]) must be searched in the conversion of the enzyme-substrate complex to products. In other words, the decrease in appVmax by increasing [I] must be less steep than the appKM decrease. This situation may occur if the ternary complex is able to evolve to products, as it occurs for incomplete inhibitors. Here the decrease of appVmax from k+2 [maxES]= k+2 [ET]) in the absence of the inhibitor, will not tend to zero, with the increase of [I] but to appVmax =k+4 [maxESI]= k+4 [ET] (See Figure 2(B)).
The therapeutic potential of PROTACs
Published in Expert Opinion on Therapeutic Patents, 2021
Andrew B. Benowitz, Katherine L. Jones, John D. Harling
Looking forward, it may be easier to demonstrate clear clinical differentiation with PROTACs versus inhibitors by focusing on targets which possess important non-catalytic scaffolding functions which are not modulated by inhibitors, but which would be affected by a degradation strategy. Alternatively, focusing on so-called ‘undruggable’ targets that have so far proven to be intractable to inhibition may be possible with PROTACs, since the PROTAC mechanism of action only requires an affinity binder to trigger the degradation of a target POI. While identifying such binders may be challenging for low tractability targets, the use of affinity-based screening methods such as DNA-encoded libraries may make this a more feasible proposition. Additionally, if sufficiently cooperative PROTAC ternary complexes can be created and optimized, affinity ligands with only modest binding potency may still be able to engage in productive ternary complex formation, further widening the scope of chemical matter that can be used to tackle low-tractability targets.