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

Journal Article · · Nature Communications
DOI:https://doi.org/10.1038/ncomms14932· OSTI ID:1355041
 [1];  [2];  [3];  [2];  [4];  [5];  [6];  [7];  [8];  [5];  [3];  [1];  [2]
  1. Univ. of Tokyo (Japan)
  2. National Inst. of Health, Rockville, MD (United States)
  3. New England Biolabs, Ipswich, MA (United States)
  4. National Inst. of Standards and Technology (NIST), Gaithersburg, MD (United States)
  5. Univ. of Kansas, Lawrence, KS (United States)
  6. Univ. of the Sciences, Philadelphia, PA (United States); National Inst. of Health (NIH), Bethesda, MD (United States)
  7. Argonne National Lab. (ANL), Argonne, IL (United States)
  8. National Inst. of Health (NIH), Bethesda, MD (United States)

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institute of General Medical Sciences; National Inst. of Health
Grant/Contract Number:
AC02-06CH11357; P30GM110761
OSTI ID:
1355041
Journal Information:
Nature Communications, Vol. 8, Issue 1; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 31 works
Citation information provided by
Web of Science

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Design of a Short Thermally Stable α-Helix Embedded in a Macrocycle journal March 2018
Thioether Macrocyclic Peptides Selected against TET1 Compact Catalytic Domain Inhibit TET1 Catalytic Activity journal April 2018
A Case Study on the Keap1 Interaction with Peptide Sequence Epitopes Selected by the Peptidomic mRNA Display journal June 2019
Max-Bergmann award lecture:A RaPID way to discover bioactive nonstandard peptides assisted by the flexizyme and FIT systems journal January 2018
Structural characterization, biochemical, inhibition and computational studies of Entamoeba histolytica phosphoglycerate mutase: finding hits for a new antiamoebic drug journal May 2018
Ribosomal synthesis and folding of peptide-helical aromatic foldamer hybrids journal March 2018
Macrocyclic peptide-based inhibition and imaging of hepatocyte growth factor journal May 2019
De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells posted_content November 2019
Quantitative high-throughput screening assays for the discovery and development of SIRPα-CD47 interaction inhibitors journal July 2019
Structural Features and Binding Modes of Thioether-Cyclized Peptide Ligands journal December 2018
Engineering Translation Components Improve Incorporation of Exotic Amino Acids journal January 2019
Quantitative evaluation of the improvement in the pharmacokinetics of a nucleic acid drug delivery system by dynamic PET imaging with 18F-incorporated oligodeoxynucleotides journal April 2014
Quantitative high-throughput screening assays for the discovery and development of SIRPα-CD47 interaction inhibitors collection January 2019
De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells journal May 2020