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An expanded trove of fragment-bound structures for the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data

DOI: 10.1016/j.str.2024.05.010 DOI Help

Authors: Tamar Mehlman (CUNY Advanced Science Research Center; CUNY Graduate Center) , Helen M. Ginn (Deutsches Elektronen-Synchrotron DESY; Universität Hamburg; Diamond Light Source) , Daniel A. Keedy (CUNY Advanced Science Research Center; City College of New York; CUNY Graduate Center)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure , VOL 65

State: Published (Approved)
Published: June 2024

Open Access Open Access

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.

Journal Keywords: X-ray crystallography; fragment screening; computational crystallography; protein structure; allostery; allosteric ligands; phosphatases; PTP1B

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Medicine


Technical Areas:

Added On: 12/06/2024 08:47

Discipline Tags:

Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

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