Journal Article

PUBDB-2024-05462

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png An expanded trove of fragment-bound structures for the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data

Mehlman, T. ; Ginn, H. M.CFEL*XFEL.EU*DESY* ; Keedy, D. A. (Corresponding author)

2024
Cell Press Cambridge, Mass.

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Please use a persistent id in citations: doi:10.1016/j.str.2024.05.010

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.

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Contributing Institute(s):

1. Fachgruppe DNMX (FS-CFEL-1-DNMX)

Research Program(s):

1. 633 - Life Sciences – Building Blocks of Life: Structure and Function (POF4-633) (POF4-633)
2. VH-NG-19-02 - Working with RoPE: Representation of Protein Entities (2023_IVF-VH-NG-19-02) (2023_IVF-VH-NG-19-02)
3. DFG project G:(GEPRIS)390715994 - EXC 2056: CUI: Advanced Imaging of Matter (390715994) (390715994)

Experiment(s):

1. No specific instrument

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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