Couldn’t agree more. And I think more discussion on integrating all the different methods (including bioSAXS and HDX) would be a good topic
Giovanna
> On Jul 17, 2019, at 4:18 AM, Tristan Croll <[log in to unmask]> wrote:
>
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> 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, [log in to unmask] 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 <[log in to unmask]> On Behalf Of Nukri
>>> Sanishvili
>>> Sent: 15 July 2019 23:09
>>> To: [log in to unmask]
>>> 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 <[log in to unmask]
>>> <mailto:[log in to unmask]> > 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 <[log in to unmask]
>>>>> <mailto:[log in to unmask]> > 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
>>>>> Head of the Centre for X-ray Structure Analysis
>>>>> Faculty of Chemistry
>>>>> University of Vienna
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>>> --
>>> Radu Aricescu
>>> MRC Laboratory of Molecular Biology
>>> Francis Crick Avenue
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