6BAI

Multiconformer model of apo K197C PTP1B at 100 K

Summary for 6BAI

• Entry DOI: 10.2210/pdb6bai/pdb
• Related: 6B8E 6B8T 6B8X 6B8Z 6B90 6B95
• Descriptor: Tyrosine-protein phosphatase non-receptor type 1, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL (3 entities in total)
• Functional Keywords: protein tyrosine phosphatase, ptp, protein tyrosine phosphatase 1b, ptp1b, enzyme, allostery, multitemperature, multiconformer, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 37441.67

Authors

Keedy, D.A.,Hill, Z.B.,Biel, J.T.,Kang, E.,Rettenmaier, T.J.,Brandao-Neto, J.,von Delft, F.,Wells, J.A.,Fraser, J.S. (deposition date: 2017-10-12, release date: 2018-06-20, Last modification date: 2024-05-22)

Primary citation

Keedy, D.A.,Hill, Z.B.,Biel, J.T.,Kang, E.,Rettenmaier, T.J.,Brandao-Neto, J.,Pearce, N.M.,von Delft, F.,Wells, J.A.,Fraser, J.S.
An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering.
Elife, 7:-, 2018

PubMed 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.

PubMed: 29877794
DOI: 10.7554/eLife.36307

Experimental method

X-RAY DIFFRACTION (1.95 Å)