[ccp4bb] Post-doctoral position in Porto, Portugal - REMINDER

[Pedro Pereira]

We are looking for a highly motivated post-doc to join the 
Macromolecular Structure group of i3S - Instituto de Investigação e 
Inovação em Saúde (https://www.i3s.up.pt/research-group.php?groupid=113) 
in Porto, Portugal. The position, funded for up to 13 months, is 
expected to start in May 2023.


Building on our recent work (1-6), the project aims to develop direct 
anticoagulants against alternative targets in the blood coagulation 
cascade that have not been clinically exploited to date or represent a 
completely unexplored mechanism of intervention.


Informal inquiries can be addressed to Jorge Ripoll-Rozada 
(jorge.roz...@ibmc.up.pt ) or Pedro J.B. 
Pereira (ppere...@ibmc.up.pt) .


Please note that applications will be considered ONLY if submitted 
(together with ALL accompanying documentation) before 2023/03/31, using 
the online tool at 
https://dozer.i3s.up.pt/applicationmanagement/#/addapplications/ResearcherFTC_Proj2020i3S06032023.


Further information: 
https://dozer.i3s.up.pt/fileupload/downloadfile/viewpdfnewtab/72182470deba408df576958ce5c5befa 
(in Portuguese) or 
https://dozer.i3s.up.pt/fileupload/downloadfile/viewpdfnewtab/5efe13569f63a911df16b39ab7bd8f3a 
(in English).


1- Thompson, R.E.; Liu, X.; Ripoll-Rozada, J.; Alonso-García, N.; 
Parker, B.L.; Pereira, P.J.B.; Payne, R.J. (2017) Tyrosine sulfation 
modulates activity of tick-derived thrombin inhibitors. /Nature 
Chemistry/ *9*, 909-917. DOI: 10.1038/nchem.2744


2 - Watson, E.; Liu, X.; Thompson, R.; Ripoll-Rozada, J.; Wu, M.; Alwis, 
I.; Gori, A.; Loh, C.-T.; Parker, B.; Otting, G.; Jackson, S.; Pereira, 
P.J.B.; Payne, R. (2018) Mosquito-derived anophelin sulfoproteins are 
potent anti-thrombotics. /ACS Central Science/ *4*, 468-476. DOI: 
10.1021/acscentsci.7b00612


3 - Watson, E.E.; Ripoll-Rozada, J.; Lee, A.C.; Wu. M.C.L.; Franck, C.; 
Pasch, T.; Premdjee, B.; Sayers, J.; Pinto, M.F.; Martins, P.M.; 
Jackson, S.P.; Pereira, P.J.B.; Payne, R.J. (2019) Rapid Assembly and 
Profiling of an Anticoagulant Sulfoprotein Library. /Proceedings of the 
National Academy of Sciences of the USA/ *116*, 13873-13878. DOI: 
10.1073/pnas.1905177116


4 - Calisto, B.M.; Ripoll-Rozada, J.; Dowman, L.J.; Franck, C.; Agten, 
S.M.; Parker, B.L.; Veloso, R.C.; Vale, N.; Gomes, P.; de Sanctis, D.; 
Payne, R.J.; Pereira, P.J.B. (2021) Sulfotyrosine-Mediated Recognition 
of Human Thrombin by a Tsetse Fly Anticoagulant Mimics Physiological 
Substrates. /Cell Chemical Biology/ *28*, 26-33. DOI: 
10.1016/j.chembiol.2020.10.002


5 - Agten, S.M.; Watson, E.E.; Ripoll-Rozada, J.; Dowman, L.J.; Wu, M.; 
Alwis, I.; Jackson, S.; Pereira, P.J.B.; Payne, R.J. (2021) Potent 
trivalent inhibitors of thrombin through hybridization of salivary 
sulfopeptides from hematophagous arthropods. /Angewandte Chemie 
International Edition/ *60*, 5348-5356. DOI: 10.1002/anie.202015127


6 - Dowman, L.J.; Agten, S.M.; Ripoll-Rozada, J.; Calisto, B.M.; 
Pereira, P.J.B.; Payne, R.J. (2021) Synthesis and evaluation of peptidic 
thrombin inhibitors bearing acid-stable sulfotyrosine analogues. 
/Chemical Communications/ *57*, 10923-10926. DOI: 10.1039/d1cc04742f


--
Pedro J. B. Pereira, PhD
IBMC - Biomolecular Structure Group
i3S - Macromolecular Structure Group
Rua Alfredo Allen 208
4200-135 Porto
Portugal
Tel.  +351 226 074 954
E-mail:ppere...@ibmc.up.pt



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[ccp4bb] Structural Biology facility manager, Imperial College London

[Bubeck, Doryen A]

Dear all,

Just a few days left to apply before the closing date (March 31) for this great 
opportunity at Imperial College London!


The Centre for Structural Biology (CSB) is looking to recruit a full-time 
Facility Manager on an open-ended permanent contract to work on the Imperial 
College South Kensington Campus. We are looking to recruit a candidate with 
strong research experience in X-ray crystallography who is interested in 
acquiring new skills in cryo electron microscopy. The post is shared across 
both the X-ray crystallography and cryo-electron microscopy (cryoEM) facilities 
and offers an exciting opportunity for training in the field of cryoEM. The 
post will be responsible for managing the crystallisation and X‑ray 
crystallography facility within the CSB, including the training of facility 
users. The post-holder will work closely with users to support crystallisation 
experiments and X-ray crystallographic data collection, both within the CSB and 
at synchrotrons (primarily at the Diamond Light Source). The post will support 
the operation of and training for biophysical equipment within CSB and will 
work closely with the cryoEM facility manager to support the training needs of 
the CSB user community. By joining the CSB Facilities team, the candidate will 
benefit from a comprehensive package of career development opportunities, 
including Imperial’s Leadership and Management Development, and Training the 
Trainer Programmes. You will also have the opportunity to engage in 
collaborative research projects.


To apply please see the link below:



https://www.imperial.ac.uk/jobs/description/NAT01410/structural-biology-facility-manager

Best wishes,

Doryen

___

Dr. Doryen Bubeck
Director Centre for Structural Biology
Department of Life Sciences
Imperial College London

https://www.imperial.ac.uk/people/d.bubeck
@bubecklab



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[ccp4bb] Senior Scientist position, Bristol Myers Squibb (US biopharma) - Seville, Spain

[Alejandro Panjkovich]

Dear all,

We are expanding our team and we are looking for an enthusiast
bioinformatician with expertise in structural biology and machine
learning. CITRE, a research institute in Seville, Spain, is part of
Bristol Myers Squibb, a global biopharmaceutical company. Please feel
free to distribute the job ad among colleagues:

https://careers.bms.com/jobs/R1562953?lang=en-US

Thank you and best regards,

Alejandro
--
Senior Principal Scientist, Predictive Sciences
CITRE - A Bristol Myers Squibb Company
Seville, Spain



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Re: [ccp4bb] To Trim or Not to To Trim

[James Holton]

Actually, they are not quite the same.

Members of an ensemble spread out over a supercell are equivalent to a 
conventional multi-conformer model, but only when it comes to the 
density derived from the coordinate atoms alone.  They are not the same 
when it comes to bulk solvent and also not the same when it comes to 
clashes at crystal packing interfaces.


It is actually a tricky question: if you have a 2-conformer salt bridge 
between symmetry mates, which one should be "A" or "B"? In phenix, "A" 
will clash with "A" in the symmetry mate. Refmac, as I understand it, 
checks if the occupancies of any two atoms of any conformer letter sum 
to >= 1.0. If so, they can clash.  Helen tells me Vagabond's treatment 
of such contacts is under development. A consensus has not been reached.


However, in a supercell refinement you don't have to ask this question. 
Every atom has an occupancy of 1.00 and there are no conformer letters 
(other than the default " "). Molecules then interact with their 
neighbors by the same rules as anywhere else in space.  And yes, each 
one would get its own, personal, solvent envelope.  Neat, huh?


If you want to try supercell refinement, do this:
1) expand your mtz data to P1.  Use the CCP4 "cad" program with the 
keyword "outlim space 1". Do not change the space group.
2) in a second run of "cad", change the space group to P1 and multiply 
all your Fs by the number of full unit cells you want. Lets say that is 
8.  I.E.:

 "scale file 1 8.0 0"
3) re-index this P1 mtz file with the "reindex" program, using keyword 
"reindex 2h,2k,2l". You will get a new mtz that has 2x the cell length 
along each edge, but is only 12.5% complete. Don't worry, that's going 
to be OK.
4) Now go to the *.pdb file: edit the "CRYST1" line to have the same 
cell as the new mtz, and change the space group to P1.


5) make copies of your coordinates and shift them to fill this new P1 
supercell. Note that this is not only populating all symmetry mates in 
one unit cell (total of 4 in P212121), but also making translated copies 
in the seven other unit cells. This would be 4*8 or 32 copies in all. 
How you name them depends on your personal preferences, but a simple 
approach is to give each symmetry mate its own chain ID (upper and lower 
case are allowed).  The "symgen P212121" keyword is convenient, but does 
not make any effort to pack things into a box. You need to do that 
yourself by applying various "shift 1 0 -1" like operations in pdbset.  
This might be more intuitive to do in coot.  Also, while you are doing 
this you need to decide which part of your multi-unit-cell space is 
going to correspond to your "conformer A", and which other part is going 
to be "B", and then "C", etc.  You won't be doing occupancy refinement 
here. Rather, by adjusting how many "A"s and "B"s you use to make up the 
ensemble you effectively now have 32 levels of occupancy (instead of the 
usual 100).


Important point: If you find this whole process daunting and you keep 
running out of letters in the alphabet, now you understand why the 
authors of refinement programs have not made this automatic. There are a 
VERY large number of ways to pack these slightly-different copies of 
your ASU into a supercell, and only one is "best". Yes, as Vaheh said, 
all the combinations will be equivalent when it comes to the density 
derived from coordinates, but the solvent density will be allowed to 
conform to each local environment, and your clash scores will vary.  
Which combination is "correct"?  I think that would be the one with the 
least number of clashes.  It is like a big combination lock.  But, for a 
first try, you might want to just use the "symgen" and "shift 1 0 0" 
commands, re-label all the chain IDs, then put the same confomer 
everywhere and let non-bond repulsions do their job in the subsequent 
refinement.


6) give your new re-indexed mtz file and expanded-to-P1-supercell pdb 
file to your favorite refinement program.


Now for the amazing part: this actually works.  At least refmac5, 
phenix.refine and shelxl (in my hands) have absolutely no problem 
refining this highly "redundant" model against data that are only 12.5% 
complete.  They don't complain at all!  Your R factors and geometry 
scores will be stable, but hopefully at least a little better than if 
you used a conventional, single-ASU ensemble.  You might think it would 
be a good idea to fill all the "missing" HKLs with zeroes.  Do not do 
this.  Phenix.refine hates it and refmac5 only barely tolerates it.  You 
might also think that with so many "free parameters" that your Rwork 
would drop to zero right away (leaving Rfree far behind) but in practice 
that does not happen.


Very important: DO NOT LOOK AT THE MAPS that come out of this kind of 
refinement. Not directly. They will look all weird and distorted. You 
need to average over all the ASUs to recover interpretable 2Fo-Fc and 
Fo-Fc maps. The strictly correct way to do this is to cu

Re: [ccp4bb] Attention APS users - where will you go?

[James Holton]

It is time to revive this old thread...

Although the Advanced Photon Source (Chicago) will be going down for a 
year or so starting Apr 17, the Advanced Light Source (Berkeley) will 
continue to operate ~50% of the MX and SAXS beam pipes that continue 
delivering light in the USA. Made possible by generous support from an 
NIH NIGMS P30, we of the "ALS-ENABLE" program are pleased to announce an 
upcoming webinar on April 10.


This webinar will cover capabilities at the beamlines in macromolecular 
crystallography, small angle X-ray scattering, and X-ray footprinting, 
as well as information on how to apply for beamtime. For more 
information, see the announcement here 
. 



http://als-enable.lbl.gov/wordpress/2023/03/14/als-enable-webinar-april-10th-2023/

Hope to see you there,

-James Holton
MAD Scientist


On 6/13/2022 8:16 AM, James Holton wrote:
Thank you everyone who responded to my little poll.  To summarize and 
paraphrase, most common response was:

"I haven't really thought about it."

A distant second place was:
"I don't collect data at APS, so I'll be fine. (aka I'm not worried 
about all those APS users out-competing me for time at my favorite 
beamline)



and 3rd/4th place:
"I will go 'somewhere else' "
and/or
"we have an old rotating anode we can dust off."

Noteworthy responses I did NOT get were:
"I will just use cryoEM instead for a year or two"
nor
"I will just use AlphaFold "

With all due respect to the amazing recent advances in those fields, 
it would appear X-rays still play an important role in structural 
science, and a year of no data doesn't seem to be an option for most 
labs.


However, it would appear there is not much concern in the community.  
Personally, I wonder if that is justified. From what I can tell 
looking at public-facing calendars, most MX beamlines are being used 
about 80% of the time, and the APS represents at least half of total 
capacity in the USA. So, in April, I expect demand will rise to ~160% 
of supply. That means ~60% of beam time request proposals will get 
turned down.


To try and help illustrate, we at ALS have been pasting together a 
master calendar we call the "fly chromosome chart" here:

https://als-enable.lbl.gov/wordpress/2022/05/19/dark-period/

The width of the bars is proportional to the number of beamlines 
available.  Yes, they vary widely in flux and other capabilities, but 
assignment of beam time is usually done in "shifts".  Now, try to 
picture next year when the "APS" bar is all black.  Also, what kind of 
pins and pucks do you use? For many beamlines you may have to buy 
different ones.


Looking forward to the June 21 APS/U town hall discussions, as well as 
the ACA's "Bridging the APS dark period" session.  We will definitely 
be discussing this at the Diffraction Methods GRC, which is July 
24-29, 2022.  Space is still available!


-James Holton
MAD Scientist



On 5/9/2022 3:12 PM, James Holton wrote:

Greetings all,

I was just thinking of taking a little poll. When the Advanced Photon 
Source at Argonne shuts down for the APS-U upgrade on April 17, 2023, 
it will take with it about 90,000 hours of X-ray beam time until well 
into 2024. So, if you are a routine user of APS, what are your 
plans?  Will you just stop collecting X-ray data for 12 months or so? 
Do you have a proposal lined up at another synchrotron? Is it in the 
USA? Europe? Asia? Or are you, like me, a big procrastinator and 
haven't really thought much about it?


Whatever it is, I'd like to hear from you. Either on- or off-list is 
fine. I expect this community will be interested in the digest.


-James Holton
MAD Scientist







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