7KNF

1.80A resolution structure of independent Phosphoglycerate mutase from C. elegans in complex with a macrocyclic peptide inhibitor (Ce-1 NHOH)

Summary for 7KNF

• Entry DOI: 10.2210/pdb7knf/pdb
• Descriptor: 2,3-bisphosphoglycerate-independent phosphoglycerate mutase, DTY-ASP-TYR-PRO-GLY-ASP-HIS-CYS-TYR-LEU-TYR-GLY-THR, ZINC ION, ... (6 entities in total)
• Functional Keywords: phosphoglycerate mutase, ipglycermide, peptide inhibitors, metal ion binding, isomerase
• Biological source: Caenorhabditis elegans; More
• Total number of polymer chains: 4
• Total formula weight: 122731.89

Authors

Lovell, S.,Kashipathy, M.M.,Battaile, K.P.,Weidmann, M.,Dranchak, P.,Aitha, M.,Queme, B.,Collmus, C.D.,Kanter, L.,Lamy, L.,Tao, D.,Rai, G.,Suga, H.,Inglese, J. (deposition date: 2020-11-04, release date: 2021-04-07, Last modification date: 2023-11-15)

Primary 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.
Structure-activity relationship of ipglycermide binding to phosphoglycerate mutases.
J.Biol.Chem., 296:100628-100628, 2021

PubMed 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 Zn 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.

PubMed: 33812994
DOI: 10.1016/j.jbc.2021.100628

Experimental method

X-RAY DIFFRACTION (1.8 Å)