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

Nicholas M. Pearce, Anthony R. Bradley, Tobias Krojer, Brian D. Marsden, Charlotte M. Deane, Frank Von Delft

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Article number032104
JournalStructural Dynamics
Volume4
Issue number3
DOIs
Publication statusPublished - 1 May 2017
Externally publishedYes

Fingerprint Dive into the research topics of 'Partial-occupancy binders identified by the Pan-Dataset Density Analysis method offer new chemical opportunities and reveal cryptic binding sites'. Together they form a unique fingerprint.

  • Cite this