Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases.

Autor:	Yu H; Department of Chemistry, Graduate School of Sciences, The University of Tokyo, Tokyo 113-0033, Japan., Dranchak P; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, USA., Li Z; Division of Genome Biology, New England Biolabs, Ipswich, Massachusetts 01938, USA., MacArthur R; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, USA., Munson MS; National Institute of Standards and Technology, Gaithersburg, Maryland 20899, USA., Mehzabeen N; Proton Structure Laboratory, Structural Biology Center, University of Kansas, Lawrence, Kansas 66047, USA., Baird NJ; National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., Battalie KP; IMCA-CAT Advanced Photon Source, Argonne National Laboratory, Argonne, Illinois 60439, USA., Ross D; National Institute of Standards and Technology, Gaithersburg, Maryland 20899, USA., Lovell S; Proton Structure Laboratory, Structural Biology Center, University of Kansas, Lawrence, Kansas 66047, USA., Carlow CK; Division of Genome Biology, New England Biolabs, Ipswich, Massachusetts 01938, USA., Suga H; Department of Chemistry, Graduate School of Sciences, The University of Tokyo, Tokyo 113-0033, Japan., Inglese J; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, USA.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2017 Apr 03; Vol. 8, pp. 14932. Date of Electronic Publication: 2017 Apr 03.
DOI:	10.1038/ncomms14932
Abstrakt:	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 12 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.
Databáze:	MEDLINE
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