Structure-activity relationship of ipglycermide binding to phosphoglycerate mutases
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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 language | English |
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Article number | 100628 |
Journal | The Journal of Biological Chemistry |
Volume | 296 |
Number of pages | 14 |
ISSN | 0021-9258 |
DOIs | |
Publication status | Published - 2021 |
Bibliographical note
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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