5qdg Citations

An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering.

Abstract

Allostery is an inherent feature of proteins, but it remains challenging to reveal the mechanisms by which allosteric signals propagate. A clearer understanding of this intrinsic circuitry would afford new opportunities to modulate protein function. Here, we have identified allosteric sites in protein tyrosine phosphatase 1B (PTP1B) by combining multiple-temperature X-ray crystallography experiments and structure determination from hundreds of individual small-molecule fragment soaks. New modeling approaches reveal 'hidden' low-occupancy conformational states for protein and ligands. Our results converge on allosteric sites that are conformationally coupled to the active-site WPD loop and are hotspots for fragment binding. Targeting one of these sites with covalently tethered molecules or mutations allosterically inhibits enzyme activity. Overall, this work demonstrates how the ensemble nature of macromolecular structure, revealed here by multitemperature crystallography, can elucidate allosteric mechanisms and open new doors for long-range control of protein function.

Articles - 5qdg mentioned but not cited (1)

  1. An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering. Keedy DA, Hill ZB, Biel JT, Kang E, Rettenmaier TJ, Brandão-Neto J, Pearce NM, von Delft F, Wells JA, Fraser JS. Elife 7 e36307 (2018)


Reviews citing this publication (7)

  1. Advances in covalent drug discovery. Boike L, Henning NJ, Nomura DK. Nat Rev Drug Discov 21 881-898 (2022)
  2. Fragment-based covalent ligand discovery. Lu W, Kostic M, Zhang T, Che J, Patricelli MP, Jones LH, Chouchani ET, Gray NS. RSC Chem Biol 2 354-367 (2021)
  3. Harnessing Conformational Plasticity to Generate Designer Enzymes. Crean RM, Gardner JM, Kamerlin SCL. J Am Chem Soc 142 11324-11342 (2020)
  4. High throughput and quantitative enzymology in the genomic era. Mokhtari DA, Appel MJ, Fordyce PM, Herschlag D. Curr Opin Struct Biol 71 259-273 (2021)
  5. Advances in methods for atomic resolution macromolecular structure determination. Thompson MC, Yeates TO, Rodriguez JA. F1000Res 9 F1000 Faculty Rev-667 (2020)
  6. Emerging Time-Resolved X-Ray Diffraction Approaches for Protein Dynamics. Hekstra DR. Annu Rev Biophys 52 255-274 (2023)
  7. Recent applications of computational methods to allosteric drug discovery. Govindaraj RG, Thangapandian S, Schauperl M, Denny RA, Diller DJ. Front Mol Biosci 9 1070328 (2022)

Articles citing this publication (47)