7GT1
PanDDA Analysis group deposition -- Crystal structure of PTP1B in complex with FMOMB000209a
This is a non-PDB format compatible entry.
Summary for 7GT1
| Entry DOI | 10.2210/pdb7gt1/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, (2S)-2-(2-chloro-6-fluorophenyl)-2,3-dihydroquinazolin-4(1H)-one, ... (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 | 37744.40 |
| Authors | Mehlman, T.,Ginn, H.M.,Keedy, D.A. (deposition date: 2024-01-03, release date: 2024-01-24, Last modification date: 2024-04-24) |
| Primary citation | Mehlman, T.S.,Ginn, H.M.,Keedy, D.A. An expanded view of ligandability in the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data. Biorxiv, 2024 Cited by PubMed Abstract: The recent advent of crystallographic small-molecule fragment screening presents the opportunity to obtain unprecedented numbers of ligand-bound protein crystal structures from a single high-throughput experiment, mapping ligandability across protein surfaces and identifying useful chemical footholds for structure-based drug design. However, due to the low binding affinities of most fragments, detecting bound fragments from crystallographic datasets has been a challenge. Here we report a trove of 65 new fragment hits across 59 new liganded crystal structures 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 validates another new binding site recently identified by simulations, one that links adjacent allosteric sites, and, perhaps most strikingly, a fragment that induces long-range allosteric protein conformational responses via a previously unreported intramolecular conduit. 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: 38260327DOI: 10.1101/2024.01.05.574428 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.91 Å) |
Structure validation
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