ORCID Profile
0000-0003-1123-7241
Current Organisation
European Synchrotron Radiation Facility
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Publisher: MDPI AG
Date: 19-09-2018
DOI: 10.20944/PREPRINTS201809.0383.V1
Abstract: The XChem facility at Diamond Light Source offers fragment screening by X-ray crystallography as a general access user program. & nbsp The main advantage of X-ray crystallography as a primary fragment screen is that it yields directly the location and pose of the fragment hits, whether within pockets of interest or merely on surface sites:& nbsp this is the key information for structure-based design and for enabling synthesis of follow-up molecules. Extensive streamlining of the screening experiment at XChem has engendered a very active user programme that is generating large amounts of data: & nbsp in 2017, 36 academic and industry groups generated 35,000 datasets of uniquely soaked crystals. & nbsp It has also generated a large number of learnings concerning the main remaining bottleneck, namely obtaining a suitable crystal system that will support a successful fragment screen.& nbsp Here we discuss the practicalities of generating screen-ready crystals that have useful electron density maps, and how to ensure they will be successfully reproduced and usable at a facility outside the home lab.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2017
DOI: 10.1038/NCOMMS15123
Abstract: In macromolecular crystallography, the rigorous detection of changed states (for ex le, ligand binding) is difficult unless signal is strong. Ambiguous (‘weak’ or ‘noisy’) density is experimentally common, since molecular states are generally only fractionally present in the crystal. Existing methodologies focus on generating maximally accurate maps whereby minor states become discernible in practice, such map interpretation is disappointingly subjective, time-consuming and methodologically unsound. Here we report the PanDDA method, which automatically reveals clear electron density for the changed state—even from inaccurate maps—by subtracting a proportion of the confounding ‘ground state’ changed states are objectively identified from statistical analysis of density distributions. The method is completely general, implying new best practice for all changed-state studies, including the routine collection of multiple ground-state crystals. More generally, these results demonstrate: the incompleteness of atomic models that single data sets contain insufficient information to model them fully and that accuracy requires further map-deconvolution approaches.
Publisher: Wiley
Date: 06-10-2017
Publisher: International Union of Crystallography (IUCr)
Date: 03-2017
DOI: 10.1107/S205979831700331X
Abstract: The steady expansion in the capacity of modern beamlines for high-throughput data collection, enabled by increasing X-ray brightness, capacity of robotics and detector speeds, has pushed the bottleneck upstream towards s le preparation. Even in ligand-binding studies using crystal soaking, the experiment best able to exploit beamline capacity, a primary limitation is the need for gentle and nontrivial soaking regimens such as stepwise concentration increases, even for robust and well characterized crystals. Here, the use of acoustic droplet ejection for the soaking of protein crystals with small molecules is described, and it is shown that it is both gentle on crystals and allows very high throughput, with 1000 unique soaks easily performed in under 10 min. In addition to having very low compound consumption (tens of nanolitres per s le), the positional precision of acoustic droplet ejection enables the targeted placement of the compound/solvent away from crystals and towards drop edges, allowing gradual diffusion of solvent across the drop. This ensures both an improvement in the reproducibility of X-ray diffraction and increased solvent tolerance of the crystals, thus enabling higher effective compound-soaking concentrations. The technique is detailed here with ex les from the protein target JMJD2D, a histone lysine demethylase with roles in cancer and the focus of active structure-based drug-design efforts.
Publisher: Elsevier
Date: 2018
DOI: 10.1016/BS.MIE.2018.09.027
Abstract: The XChem facility at Diamond Light Source offers fragment screening by X-ray crystallography as a general access user program. The main advantage of X-ray crystallography as a primary fragment screen is that it yields directly the location and pose of the fragment hits, whether within pockets of interest or merely on surface sites: this is the key information for structure-based design and for enabling synthesis of follow-up molecules. Extensive streamlining of the screening experiment at XChem has engendered a very active user program that is generating large amounts of data: in 2017, 36 academic and industry groups generated 35,000 datasets of uniquely soaked crystals. It has also generated a large number of learnings concerning the main remaining bottleneck, namely, obtaining a suitable crystal system that will support a successful fragment screen. Here we discuss the practicalities of generating screen-ready crystals that have useful electron density maps, and how to ensure they will be successfully reproduced and usable at a facility outside the home lab.
Publisher: International Union of Crystallography (IUCr)
Date: 24-02-2017
DOI: 10.1107/S2059798316020234
Abstract: XChemExplorer ( XCE ) is a data-management and workflow tool to support large-scale simultaneous analysis of protein–ligand complexes during structure-based ligand discovery (SBLD). The user interfaces of established crystallographic software packages such as CCP 4 [Winn et al. (2011), Acta Cryst. D 67 , 235–242] or PHENIX [Adams et al. (2010), Acta Cryst. D 66 , 213–221] have entrenched the paradigm that a `project' is concerned with solving one structure. This does not hold for SBLD, where many almost identical structures need to be solved and analysed quickly in one batch of work. Functionality to track progress and annotate structures is essential. XCE provides an intuitive graphical user interface which guides the user from data processing, initial map calculation, ligand identification and refinement up until data dissemination. It provides multiple entry points depending on the need of each project, enables batch processing of multiple data sets and records metadata, progress and annotations in an SQLite database. XCE is freely available and works on any Linux and Mac OS X system, and the only dependency is to have the latest version of CCP 4 installed. The design and usage of this tool are described here, and its usefulness is demonstrated in the context of fragment-screening c aigns at the Diamond Light Source. It is routinely used to analyse projects comprising 1000 data sets or more, and therefore scales well to even very large ligand-design projects.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C5SC03115J
Abstract: High concentration crystal soaking of poised fragments and one-step elaboration identified compound 17 as an inhibitor of the PHIP(2) bromodomain.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Romain Talon.