Partial-occupancy binders identified by the Pan-Dataset Density Analysis method offer new chemical opportunities and reveal cryptic binding sites

نویسندگان

  • Nicholas M. Pearce
  • Anthony R. Bradley
  • Tobias Krojer
  • Brian D. Marsden
  • Charlotte M. Deane
  • Frank von Delft
چکیده

Crystallographic fragment screening uses low molecular weight compounds to probe the protein surface and although individual protein-fragment interactions are high quality, fragments commonly bind at low occupancy, historically making identification difficult. However, our new Pan-Dataset Density Analysis method readily identifies binders missed by conventional analysis: for fragment screening data of lysine-specific demethylase 4D (KDM4D), the hit rate increased from 0.9% to 10.6%. Previously unidentified fragments reveal multiple binding sites and demonstrate: the versatility of crystallographic fragment screening; that surprisingly large conformational changes are possible in crystals; and that low crystallographic occupancy does not by itself reflect a protein-ligand complex's significance.

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عنوان ژورنال:

دوره 4  شماره 

صفحات  -

تاریخ انتشار 2017