Kinetic and crystallographic studies of glucopyranosylidene spirothiohydantoin binding to glycogen phosphorylase b

Nikos G. Oikonomakos, Vicky T. Skamnaki, Erzsébet Ösz, László Szilágyi, László Somsák, Tibor Docsa, Béla Tóth, Pál Gergely

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Abstract

Glucopyranosylidene spirothiohydantoin (TH) has been identified as a potential inhibitor of both muscle and liver glycogen phosphorylase b (GPa) and shown to diminish liver GPa activity in vitro. Kinetic experiments reported here show that TH inhibits muscle GPb competitively with respect to both substrates phosphate (Ki = 2.3 μM) and glycogen (Ki = 2.8 μM). The structure of the GPb-TH complex has been determined at a resolution of 2.26 Å and refined to a crystallographic R value of 0.193 (Rfree = 0.211). The structure of GPb-TH complex reveals that the inhibitor can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure, and provides a basis of understanding potency and specificity of the inhibitor. The glucopyranose moiety makes the standard hydrogen bonds and van der Waals contacts as observed in the glucose complex, while the rigid thiohydantoin group is in a favourable electrostatic environment and makes additional polar contacts to the protein.

Original languageEnglish
Pages (from-to)261-268
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume10
Issue number2
DOIs
Publication statusPublished - Jan 1 2002

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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