7FRE

PanDDA analysis group deposition -- Crystal structure of PTP1B after initial refinement with no ligand modeled

Summary for 7FRE

• Entry DOI: 10.2210/pdb7fre/pdb
• Group deposition: PanDDA analysis group deposition of ground-state model (G_1002253)
• Descriptor: Tyrosine-protein phosphatase non-receptor type 1, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL (3 entities in total)
• Functional Keywords: pandda, diamond i24 fragment screening, protein tyrosine phosphatase, ptp, protein tyrosine phosphatase 1b, ptp1b, enzyme, allostery, multiconformer, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 37467.70

Authors

Mehlman, T.,Biel, J.,Azeem, S.M.,Nelson, E.R.,Hossain, S.,Dunnett, L.E.,Paterson, N.G.,Douangamath, A.,Talon, R.,Axford, D.,Orins, H.,von Delft, F.,Keedy, D.A. (deposition date: 2022-10-20, release date: 2022-11-23, Last modification date: 2024-05-22)

Primary citation

Skaist Mehlman, T.,Biel, J.T.,Azeem, S.M.,Nelson, E.R.,Hossain, S.,Dunnett, L.,Paterson, N.G.,Douangamath, A.,Talon, R.,Axford, D.,Orins, H.,von Delft, F.,Keedy, D.A.
Room-temperature crystallography reveals altered binding of small-molecule fragments to PTP1B.
Elife, 12:-, 2023

PubMed Abstract: Much of our current understanding of how small-molecule ligands interact with proteins stems from X-ray crystal structures determined at cryogenic (cryo) temperature. For proteins alone, room-temperature (RT) crystallography can reveal previously hidden, biologically relevant alternate conformations. However, less is understood about how RT crystallography may impact the conformational landscapes of protein-ligand complexes. Previously, we showed that small-molecule fragments cluster in putative allosteric sites using a cryo crystallographic screen of the therapeutic target PTP1B (Keedy et al., 2018). Here, we have performed two RT crystallographic screens of PTP1B using many of the same fragments, representing the largest RT crystallographic screens of a diverse library of ligands to date, and enabling a direct interrogation of the effect of data collection temperature on protein-ligand interactions. We show that at RT, fewer ligands bind, and often more weakly - but with a variety of temperature-dependent differences, including unique binding poses, changes in solvation, new binding sites, and distinct protein allosteric conformational responses. Overall, this work suggests that the vast body of existing cryo-temperature protein-ligand structures may provide an incomplete picture, and highlights the potential of RT crystallography to help complete this picture by revealing distinct conformational modes of protein-ligand systems. Our results may inspire future use of RT crystallography to interrogate the roles of protein-ligand conformational ensembles in biological function.

PubMed: 36881464
DOI: 10.7554/eLife.84632

Experimental method

X-RAY DIFFRACTION (1.85 Å)