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

DOI: 10.1063/1.4974176 DOI Help

Authors: Nicholas Pearce (Structural Genomics Consortium, University of Oxford) , Anthony R. Bradley (University of Oxford) , Tobias Krojer (Structural Genomics Consortium, University of Oxford) , Brian D. Marsden (Structural Genomics Consortium, University of Oxford; Kennedy Institute of Rheumatology) , Charlotte M. Deane (University of Oxford) , Frank Von Delft (Structural Genomics Consortium, University of Oxford; Diamond Light Source; University of Johannesburg)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structural Dynamics , VOL 4

State: Published (Approved)
Published: May 2017
Diamond Proposal Number(s): 8421

Open Access Open Access

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.

Journal Keywords: Binding sites; Crystal structure; Data analysis; Bound states; Computer modeling

Subject Areas: Biology and Bio-materials, Chemistry, Technique Development


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 06/03/2017 10:29

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Discipline Tags:

Biochemistry Technique Development - Life Sciences & Biotech Chemistry Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)