Coronavirus spike protein morphs into 10 different shapes to invade cells

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These are some very curious protein interactions. Quoting from the article:

"Why does the spike protein go through this many conformational changes to infect a cell? It "may be a way of the virus protecting itself from recognition by antibodies," Benton said. When the spike protein is in its closed states, it hides the site that binds with the receptor, maybe to avoid antibodies coming in and binding to that site instead, he said."

end quote

It seems unlikely that hiding from antibody responses is the reason for the conformational changes since, according to the article, the changes occur only after the spike has made contact with ACE2 and begins the changes to expose these new sites :

"They found that the spike protein undergoes shape changes as it binds to the ACE2 receptor. After the spike protein first binds, its structure becomes more open to allow for more binding..."

end quote

Since the changes appear to occur only after contact with ACE2, it seems unlikely that a vaccine for those "hidden" regions of the spike would be viable. Based on the article, such regions are not usually exposed, except during the conformational changes which occur during binding - likely too late to promote antibodies, or prevent infection. In any event, it is interesting, and spooky, that the spike undergoes such changes in order to deliver the viral genome.

Perhaps using a soluble, inactive ACE2 "mimic protein" would trick the spike into latching on to a "dead-end receptor", preventing it from entering a cell. Getting the spike to initiate these conformational changes before it can bind to the real receptor may severely limit its ability to infect cells and replicate. However, creating such a "mimic" may not be so simple. But if one could produce such a recombinant protein in large amounts, and it is safe, it could provide a cure if it is present for sufficient duration to eliminate an active infection.
 
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These are some very curious protein interactions. Quoting from the article:

"Why does the spike protein go through this many conformational changes to infect a cell? It "may be a way of the virus protecting itself from recognition by antibodies," Benton said. When the spike protein is in its closed states, it hides the site that binds with the receptor, maybe to avoid antibodies coming in and binding to that site instead, he said."

end quote

It seems unlikely that hiding from antibody responses is the reason for the conformational changes since, according to the article, the changes occur only after the spike has made contact with ACE2 and begins the changes to expose these new sites :

"They found that the spike protein undergoes shape changes as it binds to the ACE2 receptor. After the spike protein first binds, its structure becomes more open to allow for more binding..."

end quote

Since the changes appear to occur only after contact with ACE2, it seems unlikely that a vaccine for those "hidden" regions of the spike would be viable. Based on the article, such regions are not usually exposed, except during the conformational changes which occur during binding - likely too late to promote antibodies, or prevent infection. In any event, it is interesting, and spooky, that the spike undergoes such changes in order to deliver the viral genome.

Perhaps using a soluble, inactive ACE2 "mimic protein" would trick the spike into latching on to a "dead-end receptor", preventing it from entering a cell. Getting the spike to initiate these conformational changes before it can bind to the real receptor may severely limit its ability to infect cells and replicate. However, creating such a "mimic" may not be so simple. But if one could produce such a recombinant protein in large amounts, and it is safe, it could provide a cure if it is present for sufficient duration to eliminate an active infection.
Wow. As a layperson (sociology major) I find the very descriptions of these spikes (especially the illustrations) to be nauseating. But if I follow your reasoning, a focus on ACE2 proteins would be the closest yet to a front-end assault against the virus. Perhaps an infusion of especially luscious dead-end receptors could round up most of the poisons? Would new dead-end receptors be harmful to the human host? Maybe the docs can provide a balanced amount of them, same as they do with most therapeutic chemicals today.

I haven't even basic knowledge of the processes you cite but my lizard brain knows that you are on to something. Please pursue your line of thought. We need all the intelligent help we can get.
 
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Perhaps an infusion of especially luscious dead-end receptors could round up most of the poisons? Would new dead-end receptors be harmful to the human host?

As long as the fake "ACE2 trap proteins" are not toxic, there is a reasonable chance this could work. But the trap protein would have to be soluble, and so will not have the identical structure as the original, which is membrane-bound. One would have to be certain in its design that it does not itself illicit an antibody response, which would neutralize it rather quickly. It certainly looks good for a look-see from some high-brows in protein-virus interactions!

And technically, viruses are not poisons, but it sure seems reasonable to call them that, the little creeps.
 
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LOL!!! Actually, I truly believe that viruses have at least as much "right" to live here among us non-viruses as we non-viruses do. They've survived much longer through brilliant mutations than have we, after all, and maybe have earned supremacy. I'm wrapping my mind around "As long as the fake "ACE2 trap proteins are not toxic " and coming to realize that such proteins may be toxic (poisonous?) while viruses are not poisonous, chemically speaking. (Right?) And I see that "toxic" may have a different meaning to chemists than what it has to civilians, who use the term interchangeably with "poisonous."

Maybe we should dumb-down the terms a little so that non-scientists like me (not to mention our POTUS) can stay on the same page as the experts during life-or-death discussions about disease, public health, allocation of medical resources, and the costs/benefits of adequate medical care for the masses.

Please don't take my remarks as cynical or obstructionist. I'm just a fairly reasonable and bright old lady trying to understand. I'm honored that you took the time to respond to me. Here's to peace, love, and knowledge!

 
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"As long as the fake "ACE2 trap proteins are not toxic " and coming to realize that such proteins may be toxic (poisonous?)

It does not seem like an ACE2 "trap" would be toxic but we would not know unless it is tried. The real ACE2 is membrane-bound, so it does not float around in your blood. The trap would have to be inactive (no enzymatic activity) and soluble for maximal impact, and this means a "new" protein in circulation, and a lot of it to be effective.

The real ACE2 is membrane-bound, and has at least two major "domains": the internal membrane domain, and external ACE2 domain - the latter being the "working end". The only obvious way to make this work is to replicate the gene coding for the external enzymatic ACE2 domain, the part which the virus binds to. That part of ACE2 would make up the "trap", but it means that some part of the trap's surface would be new to our system - that part which was contacting with the membrane-immersed domain of the real ACE2. Making this work depends largely on the overall structure of the real ACE2 - the two domains must be mostly separate from each other.

It might be possible to mask this new area to prevent it forming antibodies, which would ruin the chances of this working. And of course the trap protein would have to retain its original conformation that it has in the membrane-bound form, also not an easy thing to accomplish.

And just a heads up - viruses are not living organisms. They are little molecular machines with genetic code and some proteins. You are right about them being here longer than we have. They almost certainly arose early in the history of life, probably evolving from mechanisms used in those early life forms, and going rouge. You know how you don't like horrible relatives visiting. Viruses are in the same category.

And it is a pleasure conversing with someone like you who is interested in science and can post rational commentary. It also gives my mind exercise to recall aspects of protein structure and function critical for any good biochemist!
 
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WOW, again!! Let me re-read that a few times, and maybe draw myself some pictures. I hope that you are among the scientists working on a vaccine and/or a cure for COVID.

Thank you for clearing up the nature of viruses. I've always assumed they were a form of life. It's scary to think how devastating they can be, considering that they are not even alive! They certainly seem somehow to have evolved processes for ensuring their own replication and endurance in the world, and that makes them seem very alive, almost sentient, indeed.

I am going to study what you have written until I can envision all the moving parts. Then I think I'll better understand the successes and failures of the interventions under development. Please keep posting! We really need the insights of real-life experts, including a healthy bit of devil's advocacy, in these unsettling times.
 
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Please keep posting!

No choice based on what I just discovered. Before, it was a lot of conjecture, with no knowledge of the ACE2 protein structure. The probability of this working just went up substantially! Was unaware of the ACE2 structure, so ran a search using nih.gov in the search to go directly to the most important data.

Below is a NIH link to a scientific article referencing ACE2's structure and its interaction with the original SARS virus's spike protein. Thought you might like to read through a real set of data, and look at the neat pictures of the ACE2 protein structure. Of course most people will not understand some of this, but there are places where it is clear what they are going about.

What matters most here is that we have the structure of ACE2 at atomic resolution, which is the ultimate. So this is all well known and would come in very handy if someone tried this notion of using a modified ACE2 viral "trap".

Of particular note is figure 6, which shows that most of the ACE2 protein is sticking way out into solution, while only a small part of it anchors the entire protein to the membrane. This is very good news for making a trap out of the large, virus binding component of ACE2, sticking out as it does. It is almost enough to give one goose bumps, this looks so good! But we must remember that many good ideas have come to naught. Time will tell, perhaps! It is not likely I am the only one to think of this.

This has been a very fruitful discussion, Wanda. Thanks for perking my interest. Please keep posting!

from nih.gov :


 
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Would like to PM you but I don't see a way to do it on this site.

Not into the social media aspect. Too many people with too many questions and issues. Don't have the time. This is as close to social media as my PCs get.

Am compelled to believe others have or will think of this idea. They have had a lot of time to ponder it, and there are plenty of clever people out there. Well, a few any way! Perhaps something will come of it when the right person reads this thread?!

And there are significant hurdles. Lots of research when the vaccine is much more likely. The ACE2 trap idea is a good plan B though. Somebody has to check it out. Might have to call around to some professionals and see what if anything has been tried.

Thanks again for your ideas and exchanges. There may be more to follow once this initial publication of the structural changes has sunk into all the experts. Sure got my attention!

Another part about the trap that is unique is that the virus is not likely to find a way to mutate around it. The ACE2 protein is human and is not prone to mutate like the virus. Any significant mutations in those inner binding sites of the spike protein would be rejected by the trap in favor of the higher binding original virions that caused the infection, meaning the trap would continue to work against all variants of the virus, now or in the future. One might need to receive another shot of traps if the virus comes back in a year or two (assuming it ever disappears), or a gene could be inserted that produces the traps.

They already have those genes for antibodies, and some are being used to allow anti SARS-CoV-2 antibodies to be produced by muscle cells. These antibodies' genes are cloned from people who were already infected and produced neutralizing antibodies. This is a form of "donor DNA". Very unique, but not likley a long term cure.

We will keep an eye on things and see what develops.
 
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Just wanted you to run with your thoughts and to get credit where it is due. I encourage you to seek out the researchers whose projects could benefit from your contribution. Very best wishes!! When the ACE2 trap attains clinical greatness I will assume that you are the brain behind the success.
 
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Just wanted you to run with your thoughts and to get credit where it is due.

As I suspected, there are clever people out there who are already working on an ACE2 trap!! A simple search gives a number of hits. The reference below is an example from one of the biggest references - Science Magazine.

(Try this search : "ACE2 as a viral trap" for more hits)

It did not actually surprise me to find others working on it, but there is considerable interest in "my" soluble trap, so while I cannot claim inventor status, it shows I haven't lost my edge! Curiously most of the hits are from just the last few months, for obvious reasons I suspect. It is likely that research on it was not substantial until the latest scourge hit us.

Now I need to do more research to find out how close someone is to my precise idea of a simple, soluble format for the trap. There appears to be a number of variants of this concept.

Science Magazine reference :

 
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Well, you certainly have not lost any edge! For just a moment, let me be your surrogate grandmother and mention that, given the competitiveness of academia, research publication, granting of patents, etc., there may be some value in keeping your ideas private until you have scoped out the progress that has been made to date. If indeed there is room for a new voice, yours should be heard. If your hypothesis turns out to be the magic bullet, you should reap the rewards. Just sayin'. Go get 'em!
 
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Nice article.

I thought it was interesting, both on the operation of the spike protein (like a vast, autonomous origami sculpture) - and the "cool" experimental/imaging method described.