7FRR

PanDDA analysis group deposition -- Crystal structure of PTP1B in complex with Z2856434906

7FRR の概要

• エントリーDOI: 10.2210/pdb7frr/pdb
• Group deposition: PanDDA analysis group deposition (G_1002255)
• 分子名称: Tyrosine-protein phosphatase non-receptor type 1, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, (benzyloxy)acetic acid, ... (4 entities in total)
• 機能のキーワード: pandda, diamond i24 fragment screening, protein tyrosine phosphatase, ptp, protein tyrosine phosphatase 1b, ptp1b, enzyme, allostery, multiconformer, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37633.88

構造登録者

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. (登録日: 2022-10-25, 公開日: 2022-11-23, 最終更新日: 2024-05-22)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.83 Å)