5T19

Structure of PTP1B complexed with N-(3'-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-4'-methyl-[1,1'-biphenyl]-4-yl)acetamide

5T19 の概要

• エントリーDOI: 10.2210/pdb5t19/pdb
• 分子名称: Tyrosine-protein phosphatase non-receptor type 1, MAGNESIUM ION, 5-[4-methyl-4'-(methylamino)[1,1'-biphenyl]-3-yl]-1lambda~6~,2,5-thiadiazolidine-1,1,3-trione, ... (5 entities in total)
• 機能のキーワード: hydrolase, protein tyrosine phosphatase, 5-(aryl)-1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide unit
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Endoplasmic reticulum membrane ; Peripheral membrane protein ; Cytoplasmic side : P18031
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38022.89

構造登録者

Laciak, A.R.,Tanner, J.J. (登録日: 2016-08-18, 公開日: 2017-04-12, 最終更新日: 2023-10-04)

主引用文献

Punthasee, P.,Laciak, A.R.,Cummings, A.H.,Ruddraraju, K.V.,Lewis, S.M.,Hillebrand, R.,Singh, H.,Tanner, J.J.,Gates, K.S.
Covalent Allosteric Inactivation of Protein Tyrosine Phosphatase 1B (PTP1B) by an Inhibitor-Electrophile Conjugate.
Biochemistry, 56:2051-2060, 2017

PubMed Abstract: Protein tyrosine phosphatase 1B (PTP1B) is a validated drug target, but it has proven difficult to develop medicinally useful, reversible inhibitors of this enzyme. Here we explored covalent strategies for the inactivation of PTP1B using a conjugate composed of an active site-directed 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxide inhibitor connected via a short linker to an electrophilic α-bromoacetamide moiety. Inhibitor-electrophile conjugate 5a caused time-dependent loss of PTP1B activity consistent with a covalent inactivation mechanism. The inactivation occurred with a second-order rate constant of (1.7 ± 0.3) × 10 M min. Mass spectrometric analysis of the inactivated enzyme indicated that the primary site of modification was C121, a residue distant from the active site. Previous work provided evidence that covalent modification of the allosteric residue C121 can cause inactivation of PTP1B [Hansen, S. K., Cancilla, M. T., Shiau, T. P., Kung, J., Chen, T., and Erlanson, D. A. (2005) Biochemistry 44, 7704-7712]. Overall, our results are consistent with an unusual enzyme inactivation process in which noncovalent binding of the inhibitor-electrophile conjugate to the active site of PTP1B protects the nucleophilic catalytic C215 residue from covalent modification, thus allowing inactivation of the enzyme via selective modification of allosteric residue C121.

PubMed: 28345882
DOI: 10.1021/acs.biochem.7b00151

実験手法

X-RAY DIFFRACTION (2.1001 Å)