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Structure–activity relationship of ipglycermide binding to phosphoglycerate mutases
- Source :
- 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
- Publication Year :
- 2021
- Publisher :
- American Society for Biochemistry and Molecular Biology, 2021.
-
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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1083351X and 00219258
- Volume :
- 296
- Database :
- OpenAIRE
- Journal :
- The Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....d8c472b6439b69a727abc2ab64fb75e3