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Elife. 2018 Jun 7;7. pii: e36307. doi: 10.7554/eLife.36307.

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

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Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States.
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States.
Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
Diamond Light Source, Didcot, United Kingdom.
Crystal and Structural Chemistry Group, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands.
Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom.
Department of Biochemistry, University of Johannesburg, Johannesburg, South Africa.
Contributed equally


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.


E. coli; allostery; human; molecular biophysics; phosphatase; protein dynamics; structural biology

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