Dear all,
Not directly related to the discussion but does anyone know of a
antiretroviral protease inhibitor that is a peptide? I am new to the
topic and read that peptides suffer from bioavailability issues. Are
there any workarounds?
best,
Abhishek
On 3/21/20, Rigden, Dan <[log in to unmask]> wrote:
> Hi James
>
>
> 5o32I is not a homolog of ORF8 - the BLAST e-value is insignificant. In
> fact, rather than the EGF-like fold of 5o32I, ORF8 has an Ig-like fold
> similar to ORF7 (for which there is a structure; 1xak).
>
>
> https://toolkit.tuebingen.mpg.de/jobs/2717885_1
>
>
> I must say I got quite excited seeing that until I noticed this pre-print
> which tells the whole story very nicely, including that key position 84....
>
>
> https://www.biorxiv.org/content/10.1101/2020.03.04.977736v1
>
>
> Best wishes
>
> Dan
>
> ________________________________
> From: CCP4 bulletin board <[log in to unmask]> on behalf of Patrick Shaw
> Stewart <[log in to unmask]>
> Sent: 21 March 2020 15:41:17
> To: [log in to unmask]
> Subject: Re: [ccp4bb] CCP4BB vs COVID19
>
>
> James, this isn't conventional structural biology, but may be of interest,
> and I haven't been able get any mainstream virologists to think about it.
>
> The protein sequences are obviously of interest, but so are the RNA
> sequences at both ends of the Covid genome, which have conserved secondary
> structure. A few years ago a paper came out suggesting that wild-type
> influenza has multiple "RNA thermometers", which may play an important role
> in the tropism of influenza. Similar mechanisms may exist in other
> respiratory viruses, including Covid.
>
> My take on this, and the relevant papers, are below.
>
> Good luck to everyone and stay well,
>
> Patrick
>
>
> https://oldwivesandvirologists.blog/Covid-19-and-the-trade-off-model-of-selection/
>
> My paper in Medical Hypotheses
> http://douglas.co.uk/f_ftp1/ShawStewart_final_1-s2.pdf
>
> Narberhaus, Franz, Torsten Waldminghaus, and Saheli Chowdhury. "RNA
> thermometers." FEMS microbiology reviews 30.1 (2006): 3-16.
>
> Chursov, Andrey, et al. "Specific temperature-induced perturbations of
> secondary mRNA structures are associated with the cold-adapted
> temperature-sensitive phenotype of influenza A virus." RNA biology 9.10
> (2012): 1266-1274.
>
> Yang, Dong, and Julian L. Leibowitz. "The structure and functions of
> coronavirus genomic 3′ and 5′ ends." Virus research 206 (2015): 120-133.
>
>
>
> On Fri, Mar 20, 2020 at 10:59 PM James Holton
> <[log in to unmask]<mailto:[log in to unmask]>> wrote:
> You might think that as a structural biologist you won't be able to do
> much about COVID-19 anytime soon, but that is not true. Yes, real-world
> therapeutics and vaccines take time, but we have already seen just how
> fast we can get started. There are 21 PDBs already and some even have
> bound ligands. Good job Frank et al. BTW! And my personal thanks to
> all of you out there who are already hard at work on this.
>
> I believe this forum is an ideal place to share information and ideas on
> the structural biology of SARS-CoV-2 as we move forward. It's a big
> virus, but there are not that many proteins in it. If all of us
> independently do the same bioinformatics and literature searches and end
> up trying exactly the same thing in every lab all over the world, then
> that would be more than unfortunate. To that end, I am personally
> interested on ORF8 for reasons I will go into below. Has anyone tried
> to solve it yet? What happened? Didn't express? Bad diffraction?
> What? Do tell.
>
> Some of us, as you may have heard, are stuck at home, our beamlines and
> labs dark while we shelter-in-place. That doesn't mean our hands are
> tied. We are still allowed to think. The fraction of the human race
> that has a snowball's chance in Hades of figuring out this bug is very
> very small. Structure may be your main skill set, but you are still a
> biologist. Do you know how to run a PCR machine? Do you know how to
> pipette? You might think that anybody can do it, but that is really not
> the case. Ever trained a new student on sterile technique? How many
> days did that take? Now remember that your student was no dummy and
> already studying biology. Everyone reading this will make an excellent
> volenteer at the very least. I'm not saying this to belittle the
> average human, only to say that we scientists, moving in the circles we
> do, often forget that we have uncommon capabilities.
>
> For example, I also believe we can be useful in assay development. The
> void left by the dearth and delay of test results has been filled with
> fear, and that is a big problem. The tests, as defined, are
> straightforward, but also extremely regimented like any good laboratory
> protocol should be. The US CDC's instructions for academic labs are here:
> https://www.cdc.gov/coronavirus/2019-nCoV/lab/index.html
> My question is: how can this test be made faster, using more commonplace
> supplies, in high-throughput mode and still valid? Not just for
> clinical but for academic use? I think more than a few people on this
> list could be regarded as experts in making a complex biochemical task
> faster, more efficient, high-throughput and nonetheless valid. Yes,
> there are other people who do virus testing for a living, but right now
> they are all rather busy. Maybe if we put our minds to it we can help?
>
> As for why ORF8. I am basing my interest on the bioinformatics done in
> this article: https://dx.doi.org/10.1093/nsr/nwaa036. Search for
> "T8517C" and you will find what I'm talking about. The authors found
> two "types" of SARS-CoV-2. They call them "S" and "L" because the only
> conserved amino acid change involved is S84L in ORF8. The "S" type is
> believed to be the ancestor of "L". What is interesting is how tightly
> linked this mutation is to a silent mutation on the other end of the
> genome: the "L" type has a faster codon for Ser in ORF1. Such tight
> coupling (r^2=0.945) means there must be significant selective pressure
> preventing both of these mutations occurring in the same virus at the
> same time. That, I believe, is interesting. Espeically since they are
> so far apart I expect this selective pressure might work in trans: as in
> a super-infection. That is, the S and L genome types may interfere with
> each other.
>
> The authors fall short of claiming evidence of interference upon
> super-infection, and indeed they have already been criticised for
> calling "L" the "aggressive" type. But it is still interesting and
> points a finger at ORF8.
>
> ORF8 has only one homolog in the PDB: 5o32 with 25% identity over a
> stretch of 60 residues. This homologous region contains the S84L site
> (Val I544 in 5o32). I had a quick look and appears to be a
> cavity-filling mutation to me. Not very big, but maybe something could
> fit in there. To be sure we'd need a structure of ORF8.
>
> Good luck to you all, and stay healthy.
>
> -James Holton
> MAD Scientist
>
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> --
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