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

Pearce NM, Bradley AR, Krojer T, Marsden BD, Deane CM, von Delft F

Struct Dyn 4 (3) 032104 [2017-05-00; online 2017-02-28]

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.

DDLS Fellow

Nicholas Pearce

PubMed 28345007

DOI 10.1063/1.4974176

Crossref 10.1063/1.4974176

pmc: PMC5336473
pii: 1.4974176

Publications 9.5.0