PXD024074

PXD024074 is an original dataset announced via ProteomeXchange.

Title	Co-dependent macrocyclic peptide interactions facilitate ipglycermide high affinity binding to phosphoglycerate mutases
Description	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.
HostingRepository	PRIDE
AnnounceDate	2021-04-06
AnnouncementXML	Submission_2021-04-06_13:48:00.479.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD024074
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Dingyin Tao
SpeciesList	scientific name: Escherichia coli; NCBI TaxID: 562; scientific name: Dirofilaria immitis; NCBI TaxID: 6287; scientific name: Caenorhabditis elegans; NCBI TaxID: 6239; scientific name: Onchocerca volvulus; NCBI TaxID: 6282; scientific name: Brugia malayi; NCBI TaxID: 6279;
ModificationList	iodoacetamide derivatized residue
Instrument	6550 iFunnel Q-TOF LC/MS

Revision	Datetime	Status	ChangeLog Entry
0	2021-02-08 22:45:10	ID requested
⏵ 1	2021-04-06 13:48:01	announced

Wiedmann M, Dranchak PK, Aitha M, Queme B, Collmus CD, Kashipathy MM, Kanter L, Lamy L, Rogers JM, Tao D, Battaile KP, Rai G, Lovell S, Suga H, Inglese J, Structure-activity relationship of ipglycermide binding to phosphoglycerate mutases. J Biol Chem, 296():100628(2021) [pubmed]

submitter keyword: phosphoglycerate mutase, cyclic peptide, proteomics, structure, interaction

Dingyin Tao
contact affiliation	NIH NCATS
contact email	dingyin.tao@nih.gov
lab head
Dingyin Tao
contact affiliation	National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS)
contact email	dingyin.tao@nih.gov
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024074
     1. Label: PRIDE project
     2. Name: Co-dependent macrocyclic peptide interactions facilitate ipglycermide high affinity binding to phosphoglycerate mutases