What is the key difference between these two types of antibodies, if both are immunoglobulin G molecules? What makes binding of one antibody inhibit any given receptor and binding of another one ends up activating the same receptor? Are any changes made in the hypervariable region of these antibodies that attribute them these opposite functional roles?
Hi Anand,
to my understanding, both types of antibody (e.g. targeting a given receptor) will bind to that receptor, however at different sites (epitopes) since the two antibodies are different clones with different hypervariable regions (HVR). Despite the fact that they may (!) have the same isotype IgG, or subtypes thereof, the HVR dictates where the antibody will bind the receptor. This can happen at the ligand-binding site of the receptor or somewhere more or less close to it (entirely depending on the HRV).
The reason why one (say Ab 1) of them will activate the receptor (agonistic) and the other (say Ab 2) will block (antagonistic) it is the following:
Binding of Ab 1 to the receptor may occur at a site that mimics a ligand-binding event, which causes a conformational change in the receptor and allows it to signal into the cell.
Ab 2 may bind the receptor even close to its ligand-binding site, but in a fashion that will NOT cause a conformational change and, hence, no signaling will occur. Due to this binding of Ab 2, any subsequent binding of a 'true' ligand is blocked, mostly due to steric hindrance, simply because the giant a** IgG molecule is blocking the way to the ligand-binding site and has a high affinity for its target epitope (as does Ab 1 for its).
In theory you could have the exact same antibody clones (with their specific HVR) but not as IgG molecules but as IgA or IgM and still they would do the exact same job, although their half-life in the system (and interaction with Fc receptors) would most likely be altered.
Hope this helps! Let me know if you have more questions. :)
Hi Anand,
to my understanding, both types of antibody (e.g. targeting a given receptor) will bind to that receptor, however at different sites (epitopes) since the two antibodies are different clones with different hypervariable regions (HVR). Despite the fact that they may (!) have the same isotype IgG, or subtypes thereof, the HVR dictates where the antibody will bind the receptor. This can happen at the ligand-binding site of the receptor or somewhere more or less close to it (entirely depending on the HRV).
The reason why one (say Ab 1) of them will activate the receptor (agonistic) and the other (say Ab 2) will block (antagonistic) it is the following:
Binding of Ab 1 to the receptor may occur at a site that mimics a ligand-binding event, which causes a conformational change in the receptor and allows it to signal into the cell.
Ab 2 may bind the receptor even close to its ligand-binding site, but in a fashion that will NOT cause a conformational change and, hence, no signaling will occur. Due to this binding of Ab 2, any subsequent binding of a 'true' ligand is blocked, mostly due to steric hindrance, simply because the giant a** IgG molecule is blocking the way to the ligand-binding site and has a high affinity for its target epitope (as does Ab 1 for its).
In theory you could have the exact same antibody clones (with their specific HVR) but not as IgG molecules but as IgA or IgM and still they would do the exact same job, although their half-life in the system (and interaction with Fc receptors) would most likely be altered.
Hope this helps! Let me know if you have more questions. :)
Ok! So we can engineer the HVR according to the desired site of binding and the antibody will function accordingly, is that right? So the activating antibody will have a HVR similar to the ligand (or just the binding part of the ligand) and inhibiting/blocking antibody will not, is that how it works?
The activating antibody will 'work' as long as the receptor 'thinks' that an appropriate ligand is binding to it. For this the HVR doesn't need to have a structure similar to any ligand as long as the HVR (or more precisely its three-dimensional protein structure) guides the antibody to a site that mimics a ligand-binding event. The structure of the antigen-binding site of the antibody compared to any potential ligand can still be very different. It's all about what the receptor 'thinks' is happening to it. A blocking antibody could even bind to the very same site an activating antibody would but fail to engage in any molecular interactions with the receptor (e.g. hydrogen bonds in the simplest case) due to an altered or missing amino acid, for instance. The antibody would bind but the receptor wouldn't realize it (hence not signal).
So yes, in theory, if you can predict the 3D protein structure of a designed HRV sequence and how and where it potentially interacts with the receptor, you could engineer an antibody that will either function in an agonistic or antagonistic manner.
- Badges
- Science topic
- Similar topics
- Biological Science
- Immunology