title: Partial-occupancy binders identified by the Pan-Dataset Density Analysis method offer new chemical opportunities and reveal cryptic binding sites.
abstract: 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.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Pearce
authors.affiliation: Structural Genomics Consortium, University of Oxford , Oxford OX3 7DQ, United Kingdom.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Bradley
authors.affiliation: Structural Genomics Consortium, University of Oxford , Oxford OX3 7DQ, United Kingdom.
authors.forename: Tobias
authors.initials: T
authors.lastname: Krojer
authors.forename: Brian D
authors.initials: BD
authors.lastname: Marsden
authors.affiliation: Department of Statistics, University of Oxford , 24-29 St Giles, Oxford OX1 3LB, United Kingdom.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Deane
authors.forename: Frank
authors.initials: F
authors.lastname: von Delft