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Protein Crystallography

The Protein Crystallography Small Research Facility (PX-SRF) is an established, state-of-the-art facility streamlined for the high through-put screening of crystallization conditions, crystal mounting, and X-ray data collection. PX-SRF has provided a high-quality protein crystallography service for both academics and industrial scientists since 2008, first as part of the former Structural Genomics Consortium (SGC), and now within the Centre for Medicines Discovery (CMD).

Our mission is to provide a complete pipeline that supports all aspects of Structural Biology within protein crystallography projects. As part of an academic institution we continually develop innovative methodologies and can provide training for experienced scientists and students.

Our data collection is done at variety of beamlines at Diamond Light Source and is processed using CCP4 Software. As the PX-SRF is part of the larger CMD SRF structure and our preferred protein supplier is the CMD Protein Production SRF. We use the Scarab data management system developed by the CMD Research Informatics SRF.

 

Our research group co-developed the XChem Fragment Screening facility at Diamond Light source and invented the Crystal Shifter, which is an x-y stage for microscope with computer software that automates everyday tasks in protien fragment screening and improves quality of experiments.Our research group co-developed the XChem Fragment Screening facility at Diamond Light source and invented the Crystal Shifter, which is an x-y stage for microscope with computer software that automates everyday tasks in protien fragment screening and improves quality of experiments.

HOW WE CAN HELP YOU

  • Walk-in facility for academic collaborators:
    • Access to crystallography equipment and facilities, including an extensive screening library
    • Diamond sample registration, and tracking of crystals using our Scarab database
    • Crystal storage and shipping to Diamond, and subsequent disposal
    • Tracking of crystals using Scarab database
    • Diamond BAG reporting
  • Crystallography as a service for academic and industrial users:
    • Crystallization of novel targets, including trouble-shooting of difficult targets
    • Reproducing published structures and internal projects
    • Hit optimisation and elaboration
    • Protein-Ligand and Protein-Protein complexes
    • LCP crystallography of membrane proteins
    • Structure solution and PDB deposition preparation
    • Project management and reporting
  • XChem:
  • Scientific support and method development, including protein engineering (in collaboration with the Protein Production SRF)

CONTACT INFORMATION

Lizbé Koekemoer (lizbe.koekemoer@cmd.ox.ac.uk)

EQUIPMENT AND CAPABILITIES

  • Formulatrix R-1000 imagers with multi-fluorescence imaging at 20°C and 4°C
  • Formulator Screenmaker
  • Rockmaker protein crystallization software including RockMaker web
  • Shifter crystal harvesting system
  • Mosquitos including LCP capability
  • Ambient and cold room mounting capabilities

 

The FORMULATOR® Screen Builder is a next-generation liquid handler specifically designed for Protein Crystallography that uses patented microfluidic technology to dispense up to 34 different ingredients.The FORMULATOR® Screen Builder is a next-generation liquid handler specifically designed for Protein Crystallography that uses patented microfluidic technology to dispense up to 34 different ingredients.

 

The SPTlabtech Mosquito adapted to set up both traditional and LCP protein crystallization experiments.The SPTlabtech Mosquito adapted to set up both traditional and LCP protein crystallization experiments.

OUR TEAM

  • Frank von Delft (PI, Professor of Structural biology)
  • Lizbé Koekemoer (Team leader)
  • Beth MacLean (Research lab engineer)
  • Nathan Wright (Research lab engineer, part-time DPhil student, inventor of the crystal shifter)
  • Xiaomin Ni (PDRA)

Protein Crystallography team

Front: Nathan Wright, Frank von Delft, Mike Fairhead

Middle: Beth MacLean, Lizbé Koekemoer

Back: Kate Kot, Melissa Marx, Xiaomin Ni

WEBINARS

SELECTED PUBLICATIONS

  1. Noske, G. D.; Song, Y.; Fernandes, R. S.; Chalk, R.; Elmassoudi, H.; Koekemoer, L.; Owen, C. D.; El-Baba, T. J.; Robinson, C. V.; Oliva, G.; Godoy, A. S. An In-Solution Snapshot of SARS-COV-2 Main Protease Maturation Process and Inhibition. Nat. Commun. 2023, 14 (1), 1545. https://doi.org/10.1038/s41467-023-37035-5.
  2. Grosjean, H.; Aimon, A.; Hassell-Hart, S.; Thompson, W.; Koekemoer, L.; Bennett, J.; Anderson, C.; FitzGerald, E. A.; Krojer, T.; Bradley, A.; Fedorov, O.; Biggin, P. C.; Spencer, J.; Delft, F. von. High-Throughput Crystallography for Rapid Fragment Growth from Crude Arrays by Low-Cost Robotics. ChemRxiv March 28, 2023. https://doi.org/10.26434/chemrxiv-2023-6m2s0.
  3. Moonshot Consortium, et al.
  4. Ye, M.; Makola, M.; Newman, J. A.; Fairhead, M.; Maclean, E.; Wright, N. D.; Koekemoer, L.; Thompson, A.; Bezerra, G. A.; Yi, G.; Li, H.; Rangel, V. L.; Mamalis, D.; Aitkenhead, H.; Davis, B. G.; Gilbert, R. J. C.; Duerr, K.; Gileadi, O.; Delft, F. von. Gluebodies Improve Crystal Reliability and Diversity through Transferable Nanobody Mutations That Introduce Constitutive Crystal Contacts. bioRxiv July 26, 2022, p 2022.07.26.501559. https://doi.org/10.1101/2022.07.26.501559.
  5. Grosjean, H.; Işık, M.; Aimon, A.; Mobley, D.; Chodera, J.; von Delft, F.; Biggin, P. C. SAMPL7 Protein-Ligand Challenge: A Community-Wide Evaluation of Computational Methods against Fragment Screening and Pose-Prediction. J. Comput. Aided Mol. Des. 2022, 36 (4), 291–311. https://doi.org/10.1007/s10822-022-00452-7.
  6. Carbery, A.; Skyner, R.; von Delft, F.; Deane, C. M. Fragment Libraries Designed to Be Functionally Diverse Recover Protein Binding Information More Efficiently Than Standard Structurally Diverse Libraries. J. Med. Chem. 2022, 65 (16), 11404–11413. https://doi.org/10.1021/acs.jmedchem.2c01004.
  7. Wright, N. D.; Collins, P.; Koekemoer, L.; Krojer, T.; Talon, R.; Nelson, E.; Ye, M.; Nowak, R.; Newman, J.; Ng, J. T.; Mitrovich, N.; Wiggers, H.; von Delft, F. The Low-Cost Shifter Microscope Stage Transforms the Speed and Robustness of Protein Crystal Harvesting. Acta Crystallogr. Sect. Struct. Biol. 2021, 77 (1), 62–74. https://doi.org/10.1107/S2059798320014114.
  8. Piticchio, S. G.; Martínez-Cartró, M.; Scaffidi, S.; Rachman, M.; Rodriguez-Arevalo, S.; Sanchez-Arfelis, A.; Escolano, C.; Picaud, S.; Krojer, T.; Filippakopoulos, P.; von Delft, F.; Galdeano, C.; Barril, X. Discovery of Novel BRD4 Ligand Scaffolds by Automated Navigation of the Fragment Chemical Space. J. Med. Chem. 2021, 64 (24), 17887–17900. https://doi.org/10.1021/acs.jmedchem.1c01108.
  9. Newman, H.; Krajnc, A.; Bellini, D.; Eyermann, C. J.; Boyle, G. A.; Paterson, N. G.; McAuley, K. E.; Lesniak, R.; Gangar, M.; von Delft, F.; Brem, J.; Chibale, K.; Schofield, C. J.; Dowson, C. G. High-Throughput Crystallography Reveals Boron-Containing Inhibitors of a Penicillin-Binding Protein with Di- and Tricovalent Binding Modes. J. Med. Chem. 2021, 64 (15), 11379–11394. https://doi.org/10.1021/acs.jmedchem.1c00717.
  10. Krojer, T.; Fraser, J. S.; von Delft, F. Discovery of Allosteric Binding Sites by Crystallographic Fragment Screening. Curr. Opin. Struct. Biol. 2020, 65, 209–216. https://doi.org/10.1016/j.sbi.2020.08.004.
  11. Gray, J. L.; von Delft, F.; Brennan, P. E. Targeting the Small GTPase Superfamily through Their Regulatory Proteins. Angew. Chem. Int. Ed. 2020, 59 (16), 6342–6366. https://doi.org/10.1002/anie.201900585.
  12. Douangamath, A.; Fearon, D.; Gehrtz, P.; Krojer, T.; Lukacik, P.; Owen, C. D.; Resnick, E.; Strain-Damerell, C.; Aimon, A.; Ábrányi-Balogh, P.; Brandão-Neto, J.; Carbery, A.; Davison, G.; Dias, A.; Downes, T. D.; Dunnett, L.; Fairhead, M.; Firth, J. D.; Jones, S. P.; Keeley, A.; Keserü, G. M.; Klein, H. F.; Martin, M. P.; Noble, M. E. M.; O’Brien, P.; Powell, A.; Reddi, R. N.; Skyner, R.; Snee, M.; Waring, M. J.; Wild, C.; London, N.; von Delft, F.; Walsh, M. A. Crystallographic and Electrophilic Fragment Screening of the SARS-CoV-2 Main Protease. Nat. Commun. 2020, 11 (1), 5047. https://doi.org/10.1038/s41467-020-18709-w.
  13. Baker, L. M.; Aimon, A.; Murray, J. B.; Surgenor, A. E.; Matassova, N.; Roughley, S. D.; Collins, P. M.; Krojer, T.; von Delft, F.; Hubbard, R. E. Rapid Optimisation of Fragments and Hits to Lead Compounds from Screening of Crude Reaction Mixtures. Commun. Chem. 2020, 3 (1), 1–11. https://doi.org/10.1038/s42004-020-00367-0.
  14. Achdout, H.; Aimon, A.; Bar-David, E.; Morris, G. M. COVID Moonshot: Open Science Discovery of SARS-CoV-2 Main Protease Inhibitors by Combining Crowdsourcing, High-Throughput Experiments, Computational Simulations, and Machine Learning. bioRxiv 2020.
  15. Collins, P. M.; Douangamath, A.; Talon, R.; Dias, A.; Brandao-Neto, J.; Krojer, T.; von Delft, F. Chapter Eleven - Achieving a Good Crystal System for Crystallographic X-Ray Fragment Screening. In Methods in Enzymology; Lesburg, C. A., Ed.; Modern Approaches in Drug Discovery; Academic Press, 2018; Vol. 610, pp 251–264. https://doi.org/10.1016/bs.mie.2018.09.027.
  16. Pearce, N. M.; Bradley, A. R.; Krojer, T.; Marsden, B. D.; Deane, C. M.; von Delft, F. Partial-Occupancy Binders Identified by the Pan-Dataset Density Analysis Method Offer New Chemical Opportunities and Reveal Cryptic Binding Sites. Struct. Dyn. 2017, 4 (3), 032104. https://doi.org/10.1063/1.4974176.
  17. Krojer, T.; Talon, R.; Pearce, N.; Collins, P.; Douangamath, A.; Brandao-Neto, J.; Dias, A.; Marsden, B.; von Delft, F. The XChemExplorer Graphical Workflow Tool for Routine or Large-Scale Protein–Ligand Structure Determination. Acta Crystallogr. Sect. Struct. Biol. 2017, 73 (3), 267–278. https://doi.org/10.1107/S2059798316020234.
  18. Collins, P. M.; Ng, J. T.; Talon, R.; Nekrosiute, K.; Krojer, T.; Douangamath, A.; Brandao-Neto, J.; Wright, N.; Pearce, N. M.; von Delft, F. Gentle, Fast and Effective Crystal Soaking by Acoustic Dispensing. Acta Crystallogr. Sect. Struct. Biol. 2017, 73 (3), 246–255. https://doi.org/10.1107/S205979831700331X.
  19. Bradley, A. R.; Echalier, A.; Fairhead, M.; Strain-Damerell, C.; Brennan, P.; Bullock, A. N.; Burgess-Brown, N. A.; Carpenter, E. P.; Gileadi, O.; Marsden, B. D.; Lee, W. H.; Yue, W.; Bountra, C.; von Delft, F. The SGC beyond Structural Genomics: Redefining the Role of 3D Structures by Coupling Genomic Stratification with Fragment-Based Discovery. Essays Biochem. 2017, 61 (5), 495–503. https://doi.org/10.1042/EBC20170051.
  20. Cox, O. B.; Krojer, T.; Collins, P.; Monteiro, O.; Talon, R.; Bradley, A.; Fedorov, O.; Amin, J.; Marsden, B. D.; Spencer, J.; von Delft, F.; Brennan, P. E. A Poised Fragment Library Enables Rapid Synthetic Expansion Yielding the First Reported Inhibitors of PHIP(2), an Atypical Bromodomain †Electronic Supplementary Information (ESI) Available. See DOI: 10.1039/C5sc03115j. Chem. Sci. 2016, 7 (3), 2322–2330. https://doi.org/10.1039/c5sc03115j.