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

Hao Yu, Patricia Dranchak, Zhiru Li, Ryan MacArthur, Matthew S. Munson, Nurjahan Mehzabeen, Nathan J. Baird, Kevin P. Battalie, David Ross, Scott Lovell, Clotilde K. S. Carlow, Hiroaki Suga () and James Inglese ()
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Hao Yu: Graduate School of Sciences, The University of Tokyo
Patricia Dranchak: National Center for Advancing Translational Sciences, National Institutes of Health
Zhiru Li: New England Biolabs
Ryan MacArthur: National Center for Advancing Translational Sciences, National Institutes of Health
Matthew S. Munson: National Institute of Standards and Technology
Nurjahan Mehzabeen: Proton Structure Laboratory, Structural Biology Center, University of Kansas
Nathan J. Baird: National Heart, Lung and Blood Institute, National Institutes of Health
Kevin P. Battalie: IMCA-CAT Advanced Photon Source, Argonne National Laboratory
David Ross: National Institute of Standards and Technology
Scott Lovell: Proton Structure Laboratory, Structural Biology Center, University of Kansas
Clotilde K. S. Carlow: New England Biolabs
Hiroaki Suga: Graduate School of Sciences, The University of Tokyo
James Inglese: National Center for Advancing Translational Sciences, National Institutes of Health

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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 >1012 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.

Date: 2017
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DOI: 10.1038/ncomms14932

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