PanDDA analysis of NUDT7 screened against DSPL and OxXChem fragment libraries

SGC Oxford has performed a crystallographic fragment screen on the human peroxisomal coenzyme A diphosphatase NUDT7 (UniProtKB - P0C024). All structures with clearly identifiable ligands were deposited in the Protein Data Bank under Group Deposition ID G_1002045. The final structures and the relevant PanDDA event maps can be found at the SGC fragment screening website. This work is part of the Target Enabling Package (TEP) program at SGC and the complete TEP for NUDT7 is will also be available on ZENODO shortly.

Experiment

Crystals were prepared at the XChem facility of the Diamond Light Source (DLS). Briefly, crystals were soaked overnight with two fragment libraries; the Diamond- SGC Poised Library set (Cox et al., 2016) and the OxXChem set with nominal fragment concentrations of 100 mM, with DMSO at 30% v/v. Additionally, a series of follow-up compounds based on an initial fragment hit was synthesized and soaked overnight with nominal compound concentrations of 30 mM, with DMSO at 30% v/v. All datasets were collected at MX beamlines at DLS. Autoprocessed datasets were analysed by Pan-Dataset Density Analysis (PanDDA) (Pearce et al., 2017). All ligands that were clearly identifiable in PanDDA event maps were modelled, refined and deposited into the PDB.

Content

This repository contains:

• all results from the PanDDA analysis, including ground-state-mean maps and PanDDA event & Z-maps for all ligand bound structures
• MTZ and AIMLESS logfiles from auto-processing
• PDB, CIF & PNG files of all the soaked compounds
• final refine.pdb and refine.mtz filess of all ligand bound structures
• all data belonging to an individual crystal can be found in processed_datasets/<crystal_ID>

References

Cox, O. B. et al. A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain. Chem. Sci. 7, 2322–2330 (2016).

Pearce, N. M. et al. A multi-crystal method for extracting obscured crystallographic states from conventionally uninterpretable electron density. Nat Commun 8, (2017).