Inhibition of Low Molecular Weight Protein Tyrosine Phosphatase by an Induced-Fit Mechanism

Rongjun He, Jifeng Wang, Zhi Hong Yu, Ruo Yu Zhang, Sijiu Liu, Li Wu, Zhong-Yin Zhang

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The low molecular weight protein tyrosine phosphatase (LMW-PTP) is a regulator of a number of signaling pathways and has been implicated as a potential target for oncology and diabetes/obesity. There is significant therapeutic interest in developing potent and selective inhibitors to control LMW-PTP activity. We report the discovery of a novel class of LMW-PTP inhibitors derived from sulfophenyl acetic amide (SPAA), some of which exhibit greater than 50-fold preference for LMW-PTP over a large panel of PTPs. X-ray crystallography reveals that binding of SPAA-based inhibitors induces a striking conformational change in the LMW-PTP active site, leading to the formation of a previously undisclosed hydrophobic pocket to accommodate the α-phenyl ring in the ligand. This induced-fit mechanism is likely a major contributor responsible for the exquisite inhibitor selectivity.

Original languageEnglish (US)
Pages (from-to)9094-9106
Number of pages13
JournalJournal of Medicinal Chemistry
Volume59
Issue number19
DOIs
StatePublished - Oct 13 2016
Externally publishedYes

Fingerprint

Protein Tyrosine Phosphatases
Molecular Weight
Amides
Acetic Acid
X Ray Crystallography
Catalytic Domain
Obesity
Ligands

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Inhibition of Low Molecular Weight Protein Tyrosine Phosphatase by an Induced-Fit Mechanism. / He, Rongjun; Wang, Jifeng; Yu, Zhi Hong; Zhang, Ruo Yu; Liu, Sijiu; Wu, Li; Zhang, Zhong-Yin.

In: Journal of Medicinal Chemistry, Vol. 59, No. 19, 13.10.2016, p. 9094-9106.

Research output: Contribution to journalArticle

He, Rongjun ; Wang, Jifeng ; Yu, Zhi Hong ; Zhang, Ruo Yu ; Liu, Sijiu ; Wu, Li ; Zhang, Zhong-Yin. / Inhibition of Low Molecular Weight Protein Tyrosine Phosphatase by an Induced-Fit Mechanism. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 19. pp. 9094-9106.
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