Achieving a good crystal system for crystallographic X-ray fragment screening

Book section

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.

Authors: Collins, P; Douangamath, A; Talon, R; Dias, A; Brandão-Neto, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Host title: Modern Approaches in Drug Discovery
• Volume: 610
• Pages: 251-264
• Series: Methods in Enzymology
• Publication date: 2018-10-15
• DOI: 10.1016/bs.mie.2018.09.027
• ISSN: 0076-6879
• ISBN: 9780128153833
• Keywords: Diamond Light Source; X-ray crystallography; protein crystallization; I04-1; fragment screening; Structural genomics consortium; XChem