Structure-activity relationship of ipglycermide binding to phosphoglycerate mutases

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  • Mareike Wiedmann
  • Patricia K Dranchak
  • Mahesh Aitha
  • Bryan Queme
  • Christopher D Collmus
  • Maithri M Kashipathy
  • Liza Kanter
  • Laurence Lamy
  • Rogers, Joseph Matthew
  • Dingyin Tao
  • Kevin P Battaile
  • Ganesha Rai
  • Scott Lovell
  • Hiroaki Suga
  • James Inglese

Human phosphoglycerate mutase (dPGM) catalysis is dependent on a 2,3-bisphosphoglycerate cofactor, while the nonhomologous isozyme in many parasitic species is cofactor-independent (iPGM). This mechanistic and phylogenetic diversity offers an opportunity for selective pharmacologic targeting of glycolysis in disease-causing organisms. We previously discovered ipglycermide, a potent inhibitor of iPGM, from a large combinatorial cyclic peptide library. To fully delineate the ipglycermide pharmacophore, herein we construct a detailed structure-activity relationship using 280 substituted ipglycermide analogs. Binding affinities of these analogs to immobilized C. elegans iPGM, measured as fold-enrichment relative to the index residue by deep sequencing of an mRNA display library, illuminated the significance of each amino acid to the pharmacophore. Using co-crystal structures and binding kinetics, we show that the high affinity of ipglycermide for iPGM orthologs, from B. malayi, O. volvulus, D. immitis, and E. coli is achieved by a co-dependence between 1) the off-rate mediated by the macrocycle Cys14 thiolate coordination to an active-site Zn2+ ion in the iPGM phosphatase domain, and 2) shape-complementarity surrounding the macrocyclic core at the phosphotransferase-phosphatase domain interface. Our results show that the high affinity binding of ipglycermide to iPGMs freezes these structurally dynamic enzymes into an inactive, stable complex.

Original languageEnglish
Article number100628
JournalThe Journal of Biological Chemistry
Number of pages14
Publication statusPublished - 2021

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Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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