Structure–activity relationship of ipglycermide binding to phosphoglycerate mutases
| Autor: | Bryan Queme, Scott Lovell, Christopher D. Collmus, Patricia Dranchak, Laurence Lamy, Joseph M. Rogers, James Inglese, Maithri M. Kashipathy, Dingyin Tao, Liza Kanter, Hiroaki Suga, Kevin P. Battaile, Mahesh Aitha, Mareike M. Wiedmann, Ganesha Rai |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Models Molecular Protein Conformation nematode infectious disease dPGM cofactor-dependent phosphoglycerate mutase Protein Data Bank (RCSB PDB) affinity selection SPR surface plasmon resonance DMSO dimethyl sulfoxide Biochemistry solid phase peptide synthesis Peptides Cyclic Cofactor Phosphoglycerate mutase 03 medical and health sciences Structure-Activity Relationship RaPID Random Non-standard Peptide Integrated Discovery SPPS solid-phase peptide synthesis PDB Protein Data Bank Catalytic Domain binding kinetics Structure–activity relationship mRNA display Animals Humans iPGM cofactor-independent phosphoglycerate mutase crystallography Molecular Biology Phylogeny Phosphoglycerate Mutase Phosphoglycerate kinase 030102 biochemistry & molecular biology biology Chemistry cyclic peptides Cell Biology glycolysis PGM phosphoglycerate mutase Receptor–ligand kinetics inhibitor 030104 developmental biology protein dynamics biology.protein Pharmacophore Research Article |
| Zdroj: | The Journal of Biological Chemistry 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, vol. 296, 100628 . https://doi.org/10.1016/j.jbc.2021.100628 |
| ISSN: | 1083-351X 0021-9258 |
| DOI: | 10.1016/j.jbc.2021.100628 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|