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An expanded trove of fragment-bound structures for the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data
Open accessPublished version of a preprint
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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Metadata
- Authors
- Mehlman, T., Ginn, H. M., & Keedy, D. A.
- Affiliations
- The Graduate Center, CUNY (US)
- Universität Hamburg (DE)
- Corresponding author
- Keedy, Daniel A.
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2024-08
- Volume
- 32
- Issue
- 8
- Pages
- 1231-1238.e4
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC11316629
- OpenAlex
- W4399492393
- Cited by
- 14
- References
- 2
- Citations by year
- 2026: 4 · 2025: 10
- FWCI
- 1.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 372 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Structure (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- PubMed Central (submittedVersion, cc-by)
- Desy publication database (The Deutsches Elektronen-Synchrotron) (submittedVersion)
- DESY Publication Database (PUBDB) (Deutsches Elektronen-Synchrotron)
- Funders
- Helmholtz Association of German Research Centres (VH-NG-19-02)
- National Institutes of Health
- National Institute of General Medical Sciences (R35 GM133769)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- PTP1B, fragment hits, allosteric enzymes, ligand binding sites, ligandability, diabetes mellitus, cancer
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