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

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.

Authors:
; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1355041
Resource Type:
Journal Article
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 8; Journal Issue: 04, 2017; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Yu, Hao, Dranchak, Patricia, Li, Zhiru, MacArthur, Ryan, Munson, Matthew S., Mehzabeen, Nurjahan, Baird, Nathan J., Battalie, Kevin P., Ross, David, Lovell, Scott, Carlow, Clotilde K. S., Suga, Hiroaki, and Inglese, James. Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases. United States: N. p., 2017. Web. doi:10.1038/ncomms14932.
Yu, Hao, Dranchak, Patricia, Li, Zhiru, MacArthur, Ryan, Munson, Matthew S., Mehzabeen, Nurjahan, Baird, Nathan J., Battalie, Kevin P., Ross, David, Lovell, Scott, Carlow, Clotilde K. S., Suga, Hiroaki, & Inglese, James. Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases. United States. doi:10.1038/ncomms14932.
Yu, Hao, Dranchak, Patricia, Li, Zhiru, MacArthur, Ryan, Munson, Matthew S., Mehzabeen, Nurjahan, Baird, Nathan J., Battalie, Kevin P., Ross, David, Lovell, Scott, Carlow, Clotilde K. S., Suga, Hiroaki, and Inglese, James. Mon . "Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases". United States. doi:10.1038/ncomms14932.
@article{osti_1355041,
title = {Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases},
author = {Yu, Hao and Dranchak, Patricia and Li, Zhiru and MacArthur, Ryan and Munson, Matthew S. and Mehzabeen, Nurjahan and Baird, Nathan J. and Battalie, Kevin P. and Ross, David and Lovell, Scott and Carlow, Clotilde K. S. and Suga, Hiroaki and Inglese, James},
abstractNote = {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.},
doi = {10.1038/ncomms14932},
journal = {Nature Communications},
issn = {2041-1723},
number = 04, 2017,
volume = 8,
place = {United States},
year = {2017},
month = {4}
}

Works referenced in this record:

Refinement of Macromolecular Structures by the Maximum-Likelihood Method
journal, May 1997

  • Murshudov, G. N.; Vagin, A. A.; Dodson, E. J.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3
  • DOI: 10.1107/S0907444996012255

Overview of the CCP 4 suite and current developments
journal, March 2011

  • Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
  • DOI: 10.1107/S0907444910045749

Developments in the CCP 4 molecular-graphics project
journal, November 2004

  • Potterton, Liz; McNicholas, Stuart; Krissinel, Eugene
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12
  • DOI: 10.1107/S0907444904023716

BALBES : a molecular-replacement pipeline
journal, December 2007

  • Long, Fei; Vagin, Alexei A.; Young, Paul
  • Acta Crystallographica Section D Biological Crystallography, Vol. 64, Issue 1
  • DOI: 10.1107/S0907444907050172

XDS
journal, January 2010

  • Kabsch, Wolfgang
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
  • DOI: 10.1107/S0907444909047337

RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies
journal, January 2014


Gradient Elution Moving Boundary Electrophoresis for High-Throughput Multiplexed Microfluidic Devices
journal, January 2007

  • Shackman, Jonathan G.; Munson, Matthew S.; Ross, David
  • Analytical Chemistry, Vol. 79, Issue 2
  • DOI: 10.1021/ac061759h

Ribosomal production and in vitro selection of natural product-like peptidomimetics: The FIT and RaPID systems
journal, April 2012


Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor
journal, July 2016

  • Kahsai, Alem W.; Wisler, James W.; Lee, Jungmin
  • Nature Chemical Biology, Vol. 12, Issue 9
  • DOI: 10.1038/nchembio.2126

MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009

  • Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
  • DOI: 10.1107/S0907444909042073

Flexizymes for genetic code reprogramming
journal, May 2011


Features and development of Coot
journal, March 2010

  • Emsley, P.; Lohkamp, B.; Scott, W. G.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
  • DOI: 10.1107/S0907444910007493

Microfluidic Analysis of Complex Samples with Minimal Sample Preparation Using Gradient Elution Moving Boundary Electrophoresis
journal, December 2009

  • Strychalski, Elizabeth A.; Henry, Alyssa C.; Ross, David
  • Analytical Chemistry, Vol. 81, Issue 24
  • DOI: 10.1021/ac902075c

Solvent content of protein crystals
journal, April 1968


PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925

An introduction to data reduction: space-group determination, scaling and intensity statistics
journal, March 2011

  • Evans, Philip R.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
  • DOI: 10.1107/S090744491003982X

Drugging Undruggable Molecular Cancer Targets
journal, January 2016


The interpretation of protein structures: Estimation of static accessibility
journal, February 1971


Expanding the Capabilities of Microfluidic Gradient Elution Moving Boundary Electrophoresis for Complex Samples
journal, August 2011

  • Strychalski, Elizabeth A.; Henry, Alyssa C.; Ross, David
  • Analytical Chemistry, Vol. 83, Issue 16
  • DOI: 10.1021/ac2011894

Automated macromolecular model building for X-ray crystallography using ARP/wARP version 7
journal, June 2008

  • Langer, Gerrit; Cohen, Serge X.; Lamzin, Victor S.
  • Nature Protocols, Vol. 3, Issue 7
  • DOI: 10.1038/nprot.2008.91

Data processing and analysis with the autoPROC toolbox
journal, March 2011

  • Vonrhein, Clemens; Flensburg, Claus; Keller, Peter
  • Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
  • DOI: 10.1107/S0907444911007773

The exploration of macrocycles for drug discovery — an underexploited structural class
journal, July 2008

  • Driggers, Edward M.; Hale, Stephen P.; Lee, Jinbo
  • Nature Reviews Drug Discovery, Vol. 7, Issue 7
  • DOI: 10.1038/nrd2590

Automatic indexing of rotation diffraction patterns
journal, February 1988


Phaser crystallographic software
journal, July 2007

  • McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
  • Journal of Applied Crystallography, Vol. 40, Issue 4
  • DOI: 10.1107/S0021889807021206

Interpreting Steep Dose-Response Curves in Early Inhibitor Discovery
journal, December 2006

  • Shoichet, Brian K.
  • Journal of Medicinal Chemistry, Vol. 49, Issue 25
  • DOI: 10.1021/jm061103g