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Struct Dyn. 2017 Feb 28;4(3):032104. doi: 10.1063/1.4974176. eCollection 2017 May.

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

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Structural Genomics Consortium, University of Oxford , Oxford OX3 7DQ, United Kingdom.
Department of Statistics, University of Oxford , 24-29 St Giles, Oxford OX1 3LB, United Kingdom.


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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