The best way against COVID19 is staying at home, staying at home, and staying at home.
Nothing else. On Fri, Mar 20, 2020, 5:59 PM James Holton <jmhol...@lbl.gov> 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 > > ######################################################################## > > To unsubscribe from the CCP4BB list, click the following link: > https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 > ######################################################################## To unsubscribe from the CCP4BB list, click the following link: https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1
