Good questions! Here are my answers. I’m not sure these are completely right, these are just my impressions:

1. I believe the answer is yes. The ligand with a higher affinity will have a more compatible shape for the receptor and may try to squeeze in, displacing another ligand.

2. I think DNA transcription happens quite soon after a particular ligands docks into a receptor, probably starting immediately.

3. Absolutely not. Ligands are always jostling with each other for binding supremacy, no matter what their affinities is for a particular receptors. A ligand with a high affinity may spend more time in a receptor but it is never there permanently.

4. Around hundreds or thousands. I’m not sure of the exact number and it definitely depends on cell type. At first researchers thought the vitamin D was only produced in the skin cells. Now they know the VDR is also present in many other tissue types including cells of the bone marrow and the endometrium. For all we know every cell type may express the VDR, it’s just that not enough research has tested for its presence in specific tissues.

5. In the nucleus. That’s why the VDR is a type 1 NUCLEAR receptor.

You’re right, most ligands can bind many different receptors. For example, 25-D binds the VDR, PPAR gamma, the alpha/beta thyroid receptors, the androgen receptor, the progesterone receptor, the glucoccorticoid receptor and others. Ligand and receptor binding is always a balancing act, with ligands constantly moving and binding into new sites.

It’s definitely possible that a ligand could bind one receptor and elicit a positive effect and bind another and elicit a negative effect. Evolutionary forces do not result in perfection. Yet as I stated at the end of the piece:

“Because evolutionary processes are ruled by chance, not everything a particular receptor or cell type does is necessarily beneficial. Yet, it can be assumed that those components of the immune system that remain with us today exist because the bulk of what they do is useful.”

Nevertheless, when deciding to use a drug for a certain purpose, it’s important to know that that same drug does not bind other receptors (besides its intended target) and produce a negative effect. That’s why molecular modeling data is so useful. Such information can simply not be obtained from a clinical trial.

Hope this helps!

Amy

I have some basic questions regarding ligands and their interactions with receptors. We know from TM’s tables that different ligands have different binding energies with various receptors. So…

1. Can ligands with higher binding energies displace others after the others “got there first”?

2. How long must a ligand dock with a receptor before DNA transcription is affected?

3. Once a high binding ligand docks with a receptor does it remain docked until the cell dies?

4. How many PXR’s or VDR’s does a cell have? One of each? Thousands of each? Variable of each?

5. Are these receptors located in the nucleus of the cell? (Or as W would say, the newculus, or new clueless).

Finally, you state that “So if a ligand binds a receptor it does so because it has evolved a shape that correlates with the receptor’s shape. It probably wouldn’t have evolved such a shape if it didn’t have some purpose for having the shape.”

This makes it sound as if a specific shape is developed for a specific binding pocket. Yet we know that a specific shape will bind with a variety of pocket shapes, each with a different level of attraction. There doesn’t seem to be a perfect ligand/receptor match, but a full range of good, fairly good, doggone good, and very strong matches.

This raises the disturbing question of a ligand that has a strong attraction to two different receptors (Or two ligands having a strong attraction for the same receptor). Could you get a situation where one pair would be a desirable effect, while the other pair produced undesirable consequences?

Thanks for suffering these questions,
Phil

Yes, a molecular model is capable of discerning interactions and relationships that sometimes simply cannot be determined by a clinical trial. It’s hard to argue with accurate mathematical data, although of course, there is always some degree of uncertainty even when it comes to modeling.

That’s why the best molecular models are, in my opinion, those that hold true in a clinical setting. And the MP is does exactly that. The treatment has allowed Dr. Marshall’s in silico model to be confirmed by the reactions of human subjects, making it even harder to contest.

Best,

Amy

I believe that when a molecule binds a receptor it inevitably changes the activity of the receptor, at least to a certain degree.

I am guilty of referring to receptors as switches, which I do in order to help the average person understand agonism and antagonism.

But in reality a receptor isn’t very much like a switch. Rather, it’s a molecule with a certain shape and it has a binding pocket where molecules with other various shapes and sizes can fit. Myriad molecules will pass by a receptor in the matter of a second but only a few might actually dock into the binding pocket. If they do, it’s because their shape is in some way compatible with the binding pocket - sort of a lock and key effect.

Then, when a molecule with a certain shape binds the receptor binding pocket the fact that a fit is established elicits a change in the shape of the receptor/ligand complex - a change in conformation. This change in shape is then going to affect what DNA the receptor transcribes.

So if a ligand binds a receptor it does so because it has evolved a shape that correlates with the receptor’s shape. It probably wouldn’t have evolved such a shape if it didn’t have some purpose for having the shape. So when it binds the receptor, a change is bound to take place.

So no, I don’t think that there are ligand/receptor interactions that don’t result in antagonism or antagonism at least to a small degree. If there are molecules that do bind receptors with no purpose then I would assume they would gradually be eliminated by evolutionary forces and are thus rare.

Best,

Amy

The mechanism needn’t be perfect. It just needs to work long enough for the organism to successfully reproduce.

I, too, often wonder why a non-agonist must automatically be an antagonist. There seems to be a lot of this sort thing going on in the Marshall Theory. Apparently the general medical assumption is that a chemical is assumed to be an antagonist if it will chemically interact with one of the receptors. All of this ligand-receptor business is about homeostasis and it appears that most of the ligand-receptors are there for negative feedback (to slow something) and it’s a rare case when they cause positive feedback.

I think in this case since the Ds will plug in there at all we have to assume they will cause negative feedback or just disrupt the system entirely because the authors would have mentioned the fact that they saw agonist behavior by the Ds.

It may be that the theory is still evolving and a cogent layman-friendly version can’t easily be produced. Every time I think I have it I discover that I have missed some key element and I really have no clue what I’m talking about…as I’m sure the next commenter will point out.

I find it curious (perhaps preposterous) that the very molecule that the PXR is supposed to eliminate can itself block that action! The creator must have been asleep at the switch when that system was designed.

Why do we assume that if a molecule is not an agonist, then it must be an antagonist? Maybe its the Switzerland of microbiology, a neutral entity.

Phil