TJ McCorvie (@allostericstate on ☁️)
@allostericstate
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Revealing the hidden world of shape shifting enzymes using Cryo-EM. Senior research associate at Newcastle University, UK.
Newcastle Upon Tyne, England
Joined January 2013
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#cryoEM
#structuralbiology
🔬🧊 A thread🧵...Due to the egregious structural data discussed a few weeks ago I feel there should be a discussion about how we could possibly improve the process in which EM maps and models are validated before deposition. /1
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When you can’t get enough of coiled coils
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Even though this 100 kDa flexibly tethered domain is stuck at 5.0 Å it's still satisfying to see how well the crystal structure fits into the density. 😀
#cryoEM
(Data collected on the York Glacios)
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Happy to report our new preprint on using cryo-EM to determine the structural basis of glycogen synthase regulation by phosphorylation and glucose-6-phosphate.
@TheYueLab
@pfizer
@CmdOxford
#cryoEM
#raredisease
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Happy to report that our new preprint from the
@TheYueLab
is now online. Here we used
#cryoEM
to understand polymerisation and regulation of cytstathionine beta-synthase (CBS), mutations of which cause classical homocystinuria.
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Along with
@durham_uni
and
@NorthumbriaUni
we have been fortunate to obtain
@BBSRC
funding to purchase a cryo-electron microscope. This will greatly support the fantastic structural biology being done in the North of England and will be an entry point for new users of cryo-EM.
A
@BBSRC
grant has led us to secure a new cryo-electron microscope.
Working with
@durham_uni
&
@NorthumbriaUni
the scope will provide molecular level imaging, helping scientists better understand a range of human diseases.
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Why is it always p53?? 😮💨 From the same authors (I don't raise concerns in public unless there is a pattern). This is just symmetric noise.
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How did this get published in Chembiochem? The atomic model clearly doesn't fit at all into the density.
#cryoem
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Yikes! Are standards evenly applied in structural biology? Guess not.
Received 19 June 2024; Received in revised form 20 June 2024; Accepted 21 June 2024
#cryoEM
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For a sub 200 kDa sample, just a screening session of 800 micrographs, 30k particles later... its bonkers how EM has progressed. 🤯
#CryoEM
🧊❄️🔬
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An amazing paper with great structures. But yikes, all those FSC curves show duplicated particles. I know its nit picky but this is the most common issue I see in cryoEM papers. My recommendation is to test different min separation distances in the Remove Duplicate Particles job.
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Would Prof Kelly
@DebKellyLab
and the first author
@MACasasanta
care to explain why these nucleocapsid maps look nothing like their 2D classes?
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Proud of Linnea Blomgren with the 1st paper from her PhD: Using cryo-EM Linnea determined the allosteric basis of regulation of human methylenetetrahydrofolate reductase by the methyl donor SAM/AdoMet & its de-methylated product SAH/AdoHcy.
#cryoEM
❄️🔬🎉
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Cryo electron tomography
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After some issues with formatting images the PhD student's paper is submitted to BioRxiv!
#cryoEM
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Glad to see this commentary from Egelman about concerning issues of the use of liquid phase EM for single particle analysis:
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@shoe0nhead
It's like moaning that a well is being made in your village to make life easier for everyone but you and the village have spent a decade walking 5 miles a day to get clean drinking water.
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Our glycogen synthase paper from the
@TheYueLab
with the
@pfizer
rare disease unit is now in published form at
@NatureSMB
!
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Unfortunately I will not be there but Linnea Blomgren from
@FroeseLab
will be at the
#CryoNET
Symposium in Stockholm presenting our structural studies on MTHFR regulation. Please drop by and see her poster!
@TheYueLab
#CryoEM
🔬❄️
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The journal BBRC has a problem with inadequate reviewing of cryo-EM maps and models:
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Happy to see recombinant glycogen synthase-glycogenin complex again from our insect cells. Now to test some large scales!
#glycotime
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Looking forward to seeing this on bioRxiv very soon....
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Party of a tetrameric metabolic enzyme collected on a Titan Krios microscope
@thermosciEMSpec
#ThermoSciCryoEM
#cryoEM
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The 15 Feb deadline is approaching to apply to the latest
@TheYueLab
#phd
project at the interface of gene editing and structural biology. The successful candidate will use
#crispr
gene editing to tag & isolate complexes for structural studies by
#cryoEM
:
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@notaxation
@louis0nfire
@RubinReport
Dave has routinely played down the pandemic. Either he’s super dumb or the money is more important to him. Either way the consequences of what he touts will lead to more situations like this for many more friends & family around the USA. He does not respect others humanity.
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@Sargon_of_Akkad
Well he means opening empty property for the victims...but yeah whatever, bullshit away Sargon.
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Tried some samples on a mass-photometry demo today. Now I want a mass photometer.
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I still see a number of FSC curves being published that show likely particle duplication. It doesn't take away from the biological insights of their associated maps but it does seem a bit odd to me that people aren't aware of pathologies that FSC curves can show.
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This is how you respond to concerns (unfounded in this case) It is highly commendable that the authors deposited raw micrographs allowing the community to confirm their findings 👏 💯I hope this leads as a prime example for similar situations.
#cryoEM
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This whole situation is ridiculous:
After months of curious eyes by many structural biologists.. even more dubious map analysis.
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Thank you everyone that replied to this! Your comments made realise that I had developed some sloppy habits and so I have changed things that looks like has solved the contamination problem.
These insect cell cultures were perfectly fine yesterday. We continually have issues here at NCL with this. Anyone ever had an issue of a fast growing contaminate and any advice how to stop this? Been doing insect cells for 10 years & it’s never been this consistently bad.
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#cryoEM
🔬🧊❄️
@TriggerLoop
This Is the Way! 💪🏻We purified endogenous TRiC chaperonin and realized after staring at the maps that the complexes had actin or tubulin inside.
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An impressive example of using CHAPS to optimise orientation bias of a small 86 kDa asymmetric CDK2 complex for cryo-EM:
Our work on determining the
#CryoEM
structure of the CDC25A-CDK2-Cyclin A complex is now available
@biorxivpreprint
! As an 86 kDa asymmetric particle this was a real challenge 😅 but super happy to share a 2.9 A structure of this major cell cycle complex
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The group who published this don’t seem to care about validating their structures. This isn’t their only one unfortunately.
OK, yeah. That's... uh... not good. 😳This map does *not* appear to belong to this protein.
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@Westandforfree1
No citations, no evidence this is harming teens, no thinking through why reducing the spread of COVID is good for us all and for those more at risk. Why do guys lie and hide behind the veneer about caring about children? You should be ashamed.
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This is bonkers.
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Crystals today...now if only EM could get to this routinely... 😬
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Another image duplication from the Kelly lab that is for two different conditions (found so many of these). Previously published in a J Vis Exp 2013 paper as liquid EM and then reused as a cryo-EM image in a Small 2019 paper
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Christmas has came early at
@TheYueLab
. Thank you
@thermosciEMSpec
for the awesome Tundra set!
@nubiosciences
@EMRSncl
@UniofNewcastle
#CryoEM
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One thing: Here are my initial tweets expressing my concerns over their p53 cryo-EM structures to the authors and institution last year for which I was blocked not only by the authors but also the Huck Institute itself.
@huckinstitutes
@mariajsolares
@PSU_HGSAC
@DebKellyLab
a look at the map and model validation shows that the reported is more than likely not p53.
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I see recently FSC plots in the published & preprint literature with curves that do not drop below correlation values of zero. I think in most incidences it is due to not removing particle duplicates. I wonder what others think? Is this a problem?
#cryoEM
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Amazing AFM images👏 Now I have a craving for a cinnamon roll.
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Nice to actually see an alternative side-chain conformation from an EM map!
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Proud of Douglas Ferreira
@_0douglas
for winning first prize for his talk at the CluB-12 & HCY 2023 conference last week!
@_cluB_12
@TheYueLab
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Very cool! Looking forward to trying this in
#RELION5
. Also very interested to see how this deals with data from 100keV systems and also in the processing of small datasets.
Now on
@biorxivpreprint
:
@kimanius
paper on
#Blush
regularisation, a machine-learning based prior in
#RELION5
trained on
@EMDB_EMPIAR
entries, which he uses to solve a
#cryoEM
data set of a 40 kDa protein:RNA complex that was previously intractable! 🤯
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This is how you do it! 🔥🔥🔬🧊
#cryoem
Behold the first pre-print from my lab at the
@ICR_London
! Together with the groups of
@SimakAli
and
@AbhayKot
, we investigated inhibitor binding and selectivity for the CDK-activating kinase, an important target for future cancer drugs, using high-resolution 🍩
#cryoEM
.
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Academia
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Finally! First remote lockdown Krios Collection at Leicester. Thanks to Christos for all his help!
@LeicStructBio
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More questions for the
@DebKellyLab
: Why does EMD-22982 look like an extracted map? What other map was it possibly extracted from?
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@SamHarrisOrg
@sullydish
@NYMag
I work in academia. This Andrew has no idea about what he’s talking about. His views seem to be an exaggeration to get attention of the general public to get views.
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All these changes have seemingly prevented the contamination. It was nice to see a yellow Sf9 pellet that’s was infected with a YFP expressing baculovirus!
#Science
🧬
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@shoe0nhead
The well takes away the hard work that you did but makes life considerably easier for everyone else. Yet you're the asshole that complains and tries to prevent it from happening because you think if people don't walk those 5 miles everyday it makes them lazy
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Ligand density and fit is non-existent. "Gossypol was strongly docked to the β5 (residues G478, R560, and E562) of ALDH1L1..." What does "strongly docked" mean??
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These insect cell cultures were perfectly fine yesterday. We continually have issues here at NCL with this. Anyone ever had an issue of a fast growing contaminate and any advice how to stop this? Been doing insect cells for 10 years & it’s never been this consistently bad.
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As an aside: I think this story is a good example of putting on grids old protein stocks from old projects.
#CryoEM
🧊❄️🔬
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1. Fresh clean lab coat. I was taking a lab coat from a communal area that others would be wearing.
2. Storing the lab coat in an autoclave bag to keep it clean for longer.
3. Using stripettes when ever taking insect cell samples out. I had been using a normal pipette and tips.
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@arthistorynews
@mikegalsworthy
Not a fan of Carl. Seems to jump to conclusions before evidence is available and puts his a role as a professor of evidence based medicine to shame. Also unfortunately he’s jumped on the contrarian bandwagon for his own gains.
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It is surprising that the OneDep server accepts half-maps with non-aligning boxes. It is concerning as it seems to affect the determined FSC curve.
@EMDB_EMPIAR
#cryoEM
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Why is it that if I apply a gaussian filter, alter the voxel values by a factor of 10, and decrease the pixel size of the older map EMD-22982 I get an identical map to EMD-24147?
#ImageForensics
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"A geometry-optimized model was then subjected to global refinement using Phenix"
Why is it always p53?? 😮💨 From the same authors (I don't raise concerns in public unless there is a pattern). This is just symmetric noise.
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More specific comments on why this data is problematic can found here: but in summary the map doesn’t have the expected secondary structure features nor does the model correlate /3
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After a very painful start on Friday we are in full swing of collecting the visiting PhD student's samples using EPU Multigrid. All just before she leaves us on Tuesday!
#lastminute
#science
#CryoEM
@eBIC_Diamond
🔬🧊❄️
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@SyntaxticMe
@Sargon_of_Akkad
Somehow I don't think housing is equivalent to having transport.
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Additionally, a culture of openly correcting data should be encouraged in the structural biology community as elegantly stated in the Thorn’s lab recent review, errors are not the exception:
How can we use insights from industry to improve error culture in structural biology? Read in our newest paper!
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@cryoEM_Papers
@rajivdbt
Dodgy looking paper. The authorship, the quality of the writing, the data, the lack of info on the processing…it is certainly not the victory the author exclaims.
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@klausenhauser
It is impressive. I do wonder what would be obtainable for like 2-3 hours/600-900 micrographs of data collection, as small preliminary datasets are best for screening sample quality in my opinion.🤔
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In my opinion there should be a rule/policy for single particle cryo EM depositions to the
@EMDB_EMPIAR
where only unaltered half-maps in their full boxes are allowed.
#cryoEM
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I'm impressed with the non-uniform refinement implemented in CryoSPARC. A combination of it with its own CTF refinement has pushed the global average resolution from 3.56 A to 3.2 A of a sample I thought I was finished with. Clearly some advantages to have with the lockdown!😅
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Using comprehensive validation job in the Phenix suite highlights the issues further with this data. The half map FSC curve is shown below along with the model to map FSC. The half-map FSC is strange in my opinion. /5
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@SyntaxticMe
@Sargon_of_Akkad
And again you're ignoring the context of why this is being suggested. People have been burnt out of their homes.
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Fantastic work showing sugar induced conformational changes:
#cryoEM
#glycotime
How can you convince a coronavirus to share its cell entry secrets?
Give it something sweet! 🍬
Using
#cryoEM
& MD, we show how a sugar-based receptor binds to the HKU1 spike and triggers opening via an allosteric mechanism (🧵).
#glycotime
#virology
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Aligned squares with the screen… this has to be a good one
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Job alert! We are looking to hire a researcher to continue our work on Freidreich's ataxia and frataxin, screening for small molecule activators of this complex bypassing the need of frataxin. Please share:
@TheYueLab
@UniofNewcastle
#cryoEM
#RareDisease
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I am fortunate to be at SSIEM 2024 in sunny Porto to present two talks on our latest published work! ☀️
@JIMD_Editors
#ssiem2024
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