5KGM

2.95A resolution structure of Apo independent phosphoglycerate mutase from C. elegans (monoclinic form)

Summary for 5KGM

• Entry DOI: 10.2210/pdb5kgm/pdb
• Related: 5KGL 5KGN
• Descriptor: 2,3-bisphosphoglycerate-independent phosphoglycerate mutase, CHLORIDE ION, MANGANESE (II) ION, ... (4 entities in total)
• Functional Keywords: metal binding, coupled enzyme assay, hts, structure activity relationship, rapid systems, high throughput enzymology, isomerase
• Biological source: Caenorhabditis elegans
• Total number of polymer chains: 2
• Total formula weight: 122028.51

Authors

Lovell, S.,Mehzabeen, N.,Battaile, K.P.,Yu, H.,Dranchak, P.,MacArthur, R.,Li, Z.,Carlow, T.,Suga, H.,Inglese, J. (deposition date: 2016-06-13, release date: 2017-04-05, Last modification date: 2023-09-27)

Primary citation

Yu, H.,Dranchak, P.,Li, Z.,MacArthur, R.,Munson, M.S.,Mehzabeen, N.,Baird, N.J.,Battalie, K.P.,Ross, D.,Lovell, S.,Carlow, C.K.,Suga, H.,Inglese, J.
Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases.
Nat Commun, 8:14932-14932, 2017

PubMed Abstract: Glycolytic interconversion of phosphoglycerate isomers is catalysed in numerous pathogenic microorganisms by a cofactor-independent mutase (iPGM) structurally distinct from the mammalian cofactor-dependent (dPGM) isozyme. The iPGM active site dynamically assembles through substrate-triggered movement of phosphatase and transferase domains creating a solvent inaccessible cavity. Here we identify alternate ligand binding regions using nematode iPGM to select and enrich lariat-like ligands from an mRNA-display macrocyclic peptide library containing >10 members. Functional analysis of the ligands, named ipglycermides, demonstrates sub-nanomolar inhibition of iPGM with complete selectivity over dPGM. The crystal structure of an iPGM macrocyclic peptide complex illuminated an allosteric, locked-open inhibition mechanism placing the cyclic peptide at the bi-domain interface. This binding mode aligns the pendant lariat cysteine thiolate for coordination with the iPGM transition metal ion cluster. The extended charged, hydrophilic binding surface interaction rationalizes the persistent challenges these enzymes have presented to small-molecule screening efforts highlighting the important roles of macrocyclic peptides in expanding chemical diversity for ligand discovery.

PubMed: 28368002
DOI: 10.1038/ncomms14932

Experimental method

X-RAY DIFFRACTION (2.95 Å)