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

DOI: 10.1016/bs.mie.2018.09.027 DOI Help

Authors: Patrick M. Collins (Diamond Light Source) , Alice Douangamath (Diamond Light Source) , Romain Talon (Diamond Light Source) , Alexandre Dias (Diamond Light Source) , Jose Brandao-neto (Diamond Light Source) , Tobias Krojer (Structural Genomics Consortium, University of Oxford,) , Frank Von Delft (Diamond Light Source)
Co-authored by industrial partner: No

Type: Book Chapter

State: Published (Approved)
Published: October 2018

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.

Journal Keywords: Fragment screening; XChem; Protein crystallization; X-ray crystallography; Diamond Light Source; I04-1; Structural genomics consortium

Subject Areas: Biology and Bio-materials, Technique Development


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