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Structure–activity relationship of ipglycermide binding to phosphoglycerate mutases
Wiedmann, Mareike Dranchak, Patricia K. Aitha, Mahesh Queme, Bryan Collmus, Christopher D. Kashipathy, Maithri M. Kanter, Liza Lamy, Laurence Rogers, Joseph M. Tao, Dingyin
Wiedmann, Mareike
Dranchak, Patricia K.
Aitha, Mahesh
Queme, Bryan
Collmus, Christopher D.
Kashipathy, Maithri M.
Kanter, Liza
Lamy, Laurence
Rogers, Joseph M.
Tao, Dingyin
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Abstract
Catalysis of human phosphoglycerate mutase is dependent on a 2,3-bisphosphoglycerate cofactor (dPGM), whereas 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 Caenorhabditis 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 cocrystal structures and binding kinetics, we show that the high affinity of ipglycermide for iPGM orthologs, from Brugia malayi, Onchocerca volvulus, Dirofilaria immitis, and Escherichia coli, is achieved by a codependence between (1) the off-rate mediated by the macrocycle Cys14 thiolate coordination to an active-site Zn2+ 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.
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Date
2021-04-01
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Elsevier
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Keywords
Affinity selection, Binding kinetics, Crystallography, Cyclic peptides, Glycolysis, Nematode, Protein dynamics, Infectious disease, Solid phase peptide synthesis, Inhibitor
Citation
Wiedmann, M., Dranchak, P. K., Aitha, M., Queme, B., Collmus, C. D., Kashipathy, M. M., Kanter, L., Lamy, L., Rogers, J. M., Tao, D., Battaile, K. P., Rai, G., Lovell, S., Suga, H., & Inglese, J. (2021). Structure-activity relationship of ipglycermide binding to phosphoglycerate mutases. The Journal of biological chemistry, 296, 100628. https://doi.org/10.1016/j.jbc.2021.100628