5KGN

1.95A resolution structure of independent phosphoglycerate mutase from C. elegans in complex with a macrocyclic peptide inhibitor (2d)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.156 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

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

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.

(2017) Nat Commun 8: 14932-14932

  • DOI: https://doi.org/10.1038/ncomms14932
  • Primary Citation of Related Structures:  
    5KGL, 5KGM, 5KGN

  • 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 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.


  • Organizational Affiliation

    Department of Chemistry, Graduate School of Sciences, The University of Tokyo, Tokyo 113-0033, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
2,3-bisphosphoglycerate-independent phosphoglycerate mutase
A, B
534Caenorhabditis elegansMutation(s): 0 
Gene Names: ipgm-1F57B10.3
EC: 5.4.2.12
UniProt
Find proteins for G5EFZ1 (Caenorhabditis elegans)
Explore G5EFZ1 
Go to UniProtKB:  G5EFZ1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupG5EFZ1
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
macrocyclic peptide inhibitor
C, D
13synthetic constructMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GOL
Query on GOL

Download Ideal Coordinates CCD File 
F [auth A],
K [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
I [auth A],
N [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
MN
Query on MN

Download Ideal Coordinates CCD File 
H [auth A],
M [auth B]
MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
E [auth A],
J [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
MG
Query on MG

Download Ideal Coordinates CCD File 
G [auth A],
L [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.156 
  • Space Group: P 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 73.782α = 90
b = 75.832β = 95.66
c = 101.42γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
Aimlessdata scaling
PHASERphasing
PDB_EXTRACTdata extraction
XDSdata reduction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-04-05
    Type: Initial release
  • Version 1.1: 2017-04-26
    Changes: Database references
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description