In Ascoidea asiatica where CUG is translated as both Leu and Ser.
Mühlhausen S., Schmitt H.D., Pan K.T., Plessmann U., Urlaub H., Hurst L.D., 
Kollmar M. Endogenous stochastic decoding of the CUG codon by competing Ser- 
and Leu-tRNAs in Ascoidea asiatica. Curr. Biol. 2018; 28:2046-2057.

Perhaps, this is not a mutation at all but points to the origin of this virus.

/Michel.

From: CCP4 bulletin board <CCP4BB@JISCMAIL.AC.UK> On Behalf Of Carter, Charlie
Sent: March 21, 2020 7:48 AM
To: CCP4BB@JISCMAIL.AC.UK
Subject: External: [ccp4bb] Fwd: [ccp4bb] CCP4BB vs COVID19




Begin forwarded message:

From: "charles w carter, jr" <cwcar...@ad.unc.edu<mailto:cwcar...@ad.unc.edu>>
Subject: Re: [ccp4bb] CCP4BB vs COVID19
Date: March 21, 2020 at 8:07:53 AM EDT
To: James Holton <jmhol...@lbl.gov<mailto:jmhol...@lbl.gov>>

Brilliant post, James. Thanks so much!

I also find what you describe interesting, because of work done by a colleague, 
Manuel Santos, who showed that in fungi,

The CUG codon is decoded in vivo as serine and not leucine in Candida albicans
MAS Santos, MF Tuite
Nucleic acids research 23 (9), 1481-1486

I may be hallucinating, but I recall something to the effect that this genetic 
ambiguity also related to the ability of Candida to adapt to life in high 
concentrations of SDS.

Charlie

On Mar 20, 2020, at 6:59 PM, James Holton 
<jmhol...@lbl.gov<mailto: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

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