Dear all,
I assume most of you are aware of the EMBL-EBI datahub which was set
up in January to provide essential virus research data to all
scientists, but in case someone missed it I would like to share the link:
https://www.ebi.ac.uk/ena/pathogens/covid-19
You can find all relevant data, from COVID-19 genome sequencing data
up to x-ray and cryo-EM structures of relevant proteins.
Stay healthy,
Nikolay
*Nikolay Dobrev *
Scientific Officer, Protein Expression and Purification Core Facility
EMBL Heidelberg, Meyerhofstraße 1, 69117 Heidelberg, Germany
T +49 6221 387 8633 | M +49 173 684 0532
twitter.com/EMBLorg <http://twitter.com/EMBLorg> |
facebook.com/embl.org <http://facebook.com/embl.org> |
youtube.com/user/emblmedia <http://youtube.com/user/emblmedia>
Visit www.embl.org/events <http://www.embl.org/events>for a complete
list of all EMBL events.
On Sun, Mar 22, 2020 at 17:26, DUMAS Philippe (IGBMC)
<p.du...@ibmc-cnrs.unistra.fr> wrote:
Relevant to the discussion:
* Cell, Vol. 110, 551–561, September 6, 2002, Copyright 2002 by
Cell Press
An RNA Thermosensor Controls Expression of Virulence Genes in
Listeria monocytogenes
* Bacterial RNA thermometers: molecular zippers and switches
Jens Kortmann and Franz Narberhaus
NATURE REVIEWS | MICROBIOLOGY VOLUME 10 | APRIL 2012 | 255
*An RNA Thermometer Activity of the West Nile Virus Genomic
30-Terminal Stem-Loop Element Modulates Viral Replication Eciency
during Host Switching
Viruses 2020, 12, 104; doi:10.3390/v12010104
* Temperature triggers immune evasion by Neisseria meningitidis
Edmund Loh1*, Elisabeth Kugelberg2*, Alexander Tracy1, Qian
Zhang2, Bridget Gollan2, Helen Ewles2, Ronald Chalmers3,
Vladimir Pelicic2 & Christoph M. Tang1,2
Nature (2013)
Philippe Dumas
------------------------------------------------------------------------
*De: *"James Holton" <jmhol...@lbl.gov <mailto:jmhol...@lbl.gov>>
*À: *"CCP4BB" <CCP4BB@JISCMAIL.AC.UK <mailto:CCP4BB@JISCMAIL.AC.UK>>
*Envoyé: *Dimanche 22 Mars 2020 16:38:28
*Objet: *Re: [ccp4bb] CCP4BB vs COVID19
Thank you Patrick,
RNA structure is still structural biology, so I think relevant
here. It seems to me that RNA as a thermometer would be an easy
hypothesis to test? Has anyone measured virulence vs temperature
in cell culture?
The 3D structure of the genome is no doublt important. I wouldn't
want to try crystallizing the whole thing, but I wonder if this
might be an excellent target for cryoEM? A challenge for that "we
can classify our way out of anything" philosophy? And the result
would most certainly be interesting.
-James Holton
MAD Scientist
On 3/21/2020 8:41 AM, Patrick Shaw Stewart wrote:
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
<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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