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 <drig...@liverpool.ac.uk> 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 <CCP4BB@JISCMAIL.AC.UK> on behalf of Patrick Shaw > Stewart <patr...@douglas.co.uk> > Sent: 21 March 2020 15:41:17 > To: CCP4BB@JISCMAIL.AC.UK > 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 > <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 > > ######################################################################## > > To unsubscribe from the CCP4BB list, click the following link: > https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 > > > -- > patr...@douglas.co.uk<mailto:patr...@douglas.co.uk> Douglas Instruments > Ltd. > Douglas House, East Garston, Hungerford, Berkshire, RG17 7HD, UK > Directors: Patrick Shaw Stewart, Peter Baldock, Stefan Kolek > > http://www.douglas.co.uk > Tel: 44 (0) 148-864-9090 US toll-free 1-877-225-2034 > Regd. England 2177994, VAT Reg. GB 480 7371 36 > > ________________________________ > > 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 > ######################################################################## To unsubscribe from the CCP4BB list, click the following link: https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1
