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

Summary for 5T19

• Entry DOI: 10.2210/pdb5t19/pdb
• Descriptor: 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)
• Functional Keywords: hydrolase, protein tyrosine phosphatase, 5-(aryl)-1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide unit
• Biological source: Homo sapiens (Human)
• Cellular location: Endoplasmic reticulum membrane ; Peripheral membrane protein ; Cytoplasmic side : P18031
• Total number of polymer chains: 1
• Total formula weight: 38022.89

Authors

Laciak, A.R.,Tanner, J.J. (deposition date: 2016-08-18, release date: 2017-04-12, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.1001 Å)