Hi Radu,
Barring some truly spectacular advances, I think that crystallography is
going to have a major role to play for a long time yet. Looking at
single-particle cryoEM, for almost every target apart from the few
ultra-rigid "rocks" the reconstruction will have a wide range of
resolutions from (near)atomic in the rigid core to fuzzy blobs out on
the floppy exterior. Yes, modern focused reconstruction techniques are
improving upon this all the time, but there will be limits - and the
problem is much more serious when it comes to electron cryo-tomography
methods where you can't simply collect more particles! I think there's
some lovely potential complementarity between cryo-EM and
crystallography here: almost by definition, these peripheral mobile
domains tend to be things that fold independently of the main body of
the complex - so why not express them independently and see if they
crystallise? That way you get the best of both worlds: the initial
cryo-EM reconstruction allows some informed decision making on what
construct(s) is/are likely to reliably crystallise, crystallisation of
those domains gives you the atomic-resolution description you need, and
modelling these back into the cryo-EM map allows you to study them in a
more natural context.
To bring things back to the original topic, I guess that's what I'd like
to see more of: rather than seeing the methods as in fundamental
competition, where are the *complementarities* between crystallography
and newer techniques?
Best regards,
Tristan
On 2019-07-17 08:43, r...@mrc-lmb.cam.ac.uk wrote:
Hi Both,
I am not questioning the PDB stats, the issue was whether (crystal)
structures
are sufficiently relevant to address biological questions and justify
the
resources. Fragment screening is one example where investment in
protein
crystallography can still be justified (for now). But it doesn't really
ask or
answer biological questions... for these, whether we like it or not,
macromolecular crystallography (or NMR, even in cell) cannot be the
future. In
my opinion :-)
Best wishes,
Radu
Stating the crystallography is dead might be a bit premature, it is
still king
for depositions.
In 2017 we had a large number of fragment screening experiments
deposited.
From: CCP4 bulletin board <CCP4BB@JISCMAIL.AC.UK> On Behalf Of Nukri
Sanishvili
Sent: 15 July 2019 23:09
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] challenges in structural biology
I know it is going to hijack the original topic but I could not
help...
“The reports of death of (macromolecular) crystallography are
greatly
exaggerated.
If we believed the prognosticators, it has been dead since the 80s
when some
folks made the claim that the only relevant structures were those
solved by
NMR.
I think we've done quite well since then...
Best,
Nukri
On Mon, Jul 15, 2019 at 3:45 PM <r...@mrc-lmb.cam.ac.uk
<mailto:r...@mrc-lmb.cam.ac.uk> > wrote:
Hi Tassos, Tim,
I wonder why would you or anyone on this list worry whether biological
questions that can be asked and answered with structures are relevant
to
justify the resources? I think there is abundant evidence that this is
the
case. Unless your point is that crystallography is now dead for all
practical
purposes... then yes, I fully agree :-) It would however be wrong to
erase its
historical contribution to understanding biology.
Best wishes,
Radu
I would wonder more if the biological questions you can *ask* with a
(crystal)
structure are sufficiently relevant to justify the resources.
Sent from my iPhone
On 15 Jul 2019, at 22:08, Tim Grüne <tim.gru...@univie.ac.at
<mailto:tim.gru...@univie.ac.at> > wrote:
Dear James,
10) are the biological questions that you can answer with a
(crystal)
structure sufficiently relevant to justify the resources?
Best,
Tim
Am 15.07.2019 21:44, schrieb Holton, James M:
Hello folks,
I have the distinct honor of chairing the next Gordon Research
Conference on Diffraction Methods in Structural Biology (July 26-31
2020). This meeting will focus on the biggest challenges currently
faced by structural biologists, and I mean actual real-world
challenges. As much as possible, these challenges will take the
form of
friendly competitions with defined parameters, data, a scoring
system,
and "winners", to be established along with other unpublished
results
only at the meeting, as is tradition at GRCs.
But what are the principle challenges in biological structure
determination today? I of course have my own ideas, but I feel
like I'm
forgetting something. Obvious choices are:
1) getting crystals to diffract better
2) building models into low-resolution maps (after failing at #1)
3) telling if a ligand is really there or not
4) the phase problem (dealing with weak signal, twinning and
pseudotranslation)
5) what does "resolution" really mean?
6) why are macromolecular R factors so much higher than
small-molecule
ones?
7) what is the best way to process serial crystallography data?
8) how should one deal with non-isomorphism in multi-crystal
methods?
9) what is the "structure" of something that won't sit still?
What am I missing? Is industry facing different problems than
academics? Are there specific challenges facing electron-based
techniques? If so, could the combined strength of all the world's
methods developers solve them? I'm interested in hearing the voice
of
this community. On or off-list is fine.
-James Holton
MAD Scientist
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Tim Gruene
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Radu Aricescu
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tel: +44-(0)1223-267049
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