6B90

Multiconformer model of apo WT PTP1B with glycerol at 100 K (ALTERNATIVE REFINEMENT OF PDB 1SUG showing conformational heterogeneity)

6B90 の概要

• エントリーDOI: 10.2210/pdb6b90/pdb
• 関連するPDBエントリー: 1sug 6B8E 6B8T 6B8X 6B8Z
• 分子名称: Tyrosine-protein phosphatase non-receptor type 1, GLYCEROL, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (4 entities in total)
• 機能のキーワード: protein tyrosine phosphatase, ptp, protein tyrosine phosphatase 1b, ptp1b, enzyme, allostery, multitemperature, multiconformer, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37948.25

構造登録者

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. (登録日: 2017-10-09, 公開日: 2018-06-20, 最終更新日: 2024-05-22)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.95 Å)