7kng | pdb_00007kng

2.10A resolution structure of independent Phosphoglycerate mutase from C. elegans in complex with a macrocyclic peptide inhibitor (Ce-2 Y7F)

spinqualitylabelsall models 7kng, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7kng is a 4 chain structure with sequence from Caenorhabditis elegans. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.1Å Ligands: ACE, CL, DTY, NA, NH2, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GPMI_CAEEL Catalyzes the interconversion of 2-phosphoglycerate and 3-phosphoglycerate. Publication Abstract from PubMed 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(2+) 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. Structure-activity relationship of ipglycermide binding to phosphoglycerate mutases.,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 J Biol Chem. 2021 Jan-Jun;296:100628. doi: 10.1016/j.jbc.2021.100628. Epub 2021 , Apr 1. PMID:33812994 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphoglycerate mutase 3D structures

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