7GT8

PanDDA Analysis group deposition -- Crystal structure of PTP1B in complex with FMSOA001439b

Summary for 7GT8

• Entry DOI: 10.2210/pdb7gt8/pdb
• Group deposition: PanDDA Analysis group deposition (G_1002284)
• Descriptor: Tyrosine-protein phosphatase non-receptor type 1, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, 5-chloranylthiophene-2-sulfonamide, ... (4 entities in total)
• Functional Keywords: pandda, diamond i04-1 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: 37665.37

Authors

Mehlman, T.,Ginn, H.M.,Keedy, D.A. (deposition date: 2024-01-03, release date: 2024-01-24, Last modification date: 2025-12-10)

Primary citation

Mehlman, T.,Ginn, H.M.,Keedy, D.A.
An expanded trove of fragment-bound structures for the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data.
Structure, 32:1231-1238.e4, 2024

PubMed Abstract: Due to their low binding affinities, detecting small-molecule fragments bound to protein structures from crystallographic datasets has been a challenge. Here, we report a trove of 65 new fragment hits for PTP1B, an "undruggable" therapeutic target enzyme for diabetes and cancer. These structures were obtained from computational analysis of data from a large crystallographic screen, demonstrating the power of this approach to elucidate many (∼50% more) "hidden" ligand-bound states of proteins. Our new structures include a fragment hit found in a novel binding site in PTP1B with a unique location relative to the active site, one that links adjacent allosteric sites, and, perhaps most strikingly, a fragment that induces long-range allosteric protein conformational responses. Altogether, our research highlights the utility of computational analysis of crystallographic data, makes publicly available dozens of new ligand-bound structures of a high-value drug target, and identifies novel aspects of ligandability and allostery in PTP1B.

PubMed: 38861991
DOI: 10.1016/j.str.2024.05.010

Experimental method

X-RAY DIFFRACTION (1.91 Å)