Distinct functional and conformational states of the human lymphoid tyrosine phosphatase catalytic domain can be targeted by choice of the inhibitor chemotype

Dušica Vidović, Yuli Xie, Alison Rinderspacher, Shi Xian Deng, Donald W. Landry, Caty Chung, Deborah H. Smith, Lutz Tautz, Stephan C Schuerer

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene, has recently been identified as a promising drug target for human autoimmunity diseases. Like the majority of protein-tyrosine phosphatases LYP can adopt two functionally distinct forms determined by the conformation of the WPD-loop. The WPD-loop plays an important role in the catalytic dephosphorylation by protein-tyrosine phosphatases. Here we investigate the binding modes of two chemotypes of small molecule LYP inhibitors with respect to both protein conformations using computational modeling. To evaluate binding in the active form, we built a LYP protein structure model of high quality. Our results suggest that the two different compound classes investigated, bind to different conformations of the LYP phosphatase domain. Binding to the closed form is facilitated by an interaction with Asp195 in the WPD-loop, presumably stabilizing the active conformation. The analysis presented here is relevant for the design of inhibitors that specifically target either the closed or the open conformation of LYP in order to achieve better selectivity over phosphatases with similar binding sites.

Original languageEnglish
Pages (from-to)873-883
Number of pages11
JournalJournal of Computer-Aided Molecular Design
Volume25
Issue number9
DOIs
StatePublished - Sep 1 2011

Fingerprint

Non-Receptor Type 22 Protein Tyrosine Phosphatase
phosphatases
tyrosine
Phosphatases
Phosphoric Monoester Hydrolases
inhibitors
Tyrosine
Catalytic Domain
Conformations
Protein Tyrosine Phosphatases
proteins
Proteins
Protein Conformation
Autoimmunity
Model structures
Binding Sites
Genes
Binding sites
genes

Keywords

  • Docking
  • Drug design
  • Homology modeling
  • LYP
  • Protein tyrosine phosphorylation
  • PTPN22

ASJC Scopus subject areas

  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Computer Science Applications

Cite this

Distinct functional and conformational states of the human lymphoid tyrosine phosphatase catalytic domain can be targeted by choice of the inhibitor chemotype. / Vidović, Dušica; Xie, Yuli; Rinderspacher, Alison; Deng, Shi Xian; Landry, Donald W.; Chung, Caty; Smith, Deborah H.; Tautz, Lutz; Schuerer, Stephan C.

In: Journal of Computer-Aided Molecular Design, Vol. 25, No. 9, 01.09.2011, p. 873-883.

Research output: Contribution to journalArticle

Vidović, Dušica ; Xie, Yuli ; Rinderspacher, Alison ; Deng, Shi Xian ; Landry, Donald W. ; Chung, Caty ; Smith, Deborah H. ; Tautz, Lutz ; Schuerer, Stephan C. / Distinct functional and conformational states of the human lymphoid tyrosine phosphatase catalytic domain can be targeted by choice of the inhibitor chemotype. In: Journal of Computer-Aided Molecular Design. 2011 ; Vol. 25, No. 9. pp. 873-883.
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