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Co-dependent macrocyclic peptide interactions facilitate ipglycermide high affinity binding to phosphoglycerate mutases

ABSTRACT: The phylogenetic divergence between parasitic and mammalian phosphoglycerate mutases (PGMs) offers an opportunity for selective pharmacologic targeting of glycolysis in disease-causing organisms. With this aim we previously described ipglycermides, discovered by affinity selection from a vast nucleic acid-encoded cyclic peptide library, as the first potent and selective class of cofactor-independent PGM (iPGM) inhibitors. From C. elegans iPGM•ipglycermide co-crystal structures we now delineate the previously hypothesized metal ion binding geometries at the ipglycermide C-terminal cysteine. To develop a baseline structure-activity relationship complementing the structural details, the 14 amino acids of ipglycermide were individually substituted creating 280 DNA-encoded analogs. Binding affinities to immobilized C. elegans iPGM, measured as fold-enrichment by deep sequencing, illuminated the significance of each amino acid sidechain to the pharmacophore and guided ipglycermides designed with improved orthologous iPGM affinity. In consideration with binding kinetics, we describe how the high affinity of ipglycermide to a range of iPGM orthologs is achieved by a co-dependence on tunable metal ion coordination-associated off-rates and induced-concavity around the macrocyclic core at the phosphotransferase-phosphatase domain interface to freeze the structurally dynamic enzyme into an inactive, stable complex.

INSTRUMENT(S): 6550 iFunnel Q-TOF LC/MS

ORGANISM(S): Brugia Malayi Escherichia Coli Dirofilaria Immitis Caenorhabditis Elegans Onchocerca Volvulus

TISSUE(S): Cell Culture

SUBMITTER: Dingyin Tao

LAB HEAD: Dingyin Tao

PROVIDER: PXD024074 | Pride | 2021-04-06

REPOSITORIES: Pride

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Structure-activity relationship of ipglycermide binding to phosphoglycerate mutases.

Wiedmann Mareike M Dranchak Patricia K PK Aitha Mahesh M Queme Bryan B Collmus Christopher D CD Kashipathy Maithri M MM Kanter Liza L Lamy Laurence L Rogers Joseph M JM Tao Dingyin D Battaile Kevin P KP Rai Ganesha G Lovell Scott S Suga Hiroaki H Inglese James J

The Journal of biological chemistry 20210101

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 phar ...[more]

PMID: 33812994

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			Action	DRS
	Sample_BM_1uL01.d.zip	Other
	Sample_BM_1uL01.mgf	Mgf
	Sample_BM_1uL01.mzid.gz	Mzid
	Sample_CLLEc_1uL01.mzid.gz	Mzid
	Sample_Ce_1uL01.d.zip	Other