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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 >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.

Authors:
 [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)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institute of General Medical Sciences; National Inst. of Health
OSTI Identifier:
1355041
Grant/Contract Number:  
AC02-06CH11357; P30GM110761
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 8; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Enzyme mechanisms; High-throughput screening; Isoenzymes; X-ray crystallography

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. https://www.osti.gov/servlets/purl/1355041.
@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 = 1,
volume = 8,
place = {United States},
year = {2017},
month = {4}
}

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Cited by: 19 works
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Works referenced in this record:

Design and synthesis of mono and bicyclic tetrapeptides thioester as potent inhibitor of histone deacetylases
journal, July 2014


Development of a mutagenesis, expression and purification system for yeast phosphoglycerate mutase. Investigation of the role of active-site His181
journal, July 1992


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

Crystal Structures of Leishmania mexicana Phosphoglycerate Mutase Suggest a One-Metal Mechanism and a New Enzyme Subclass
journal, December 2009

  • Nowicki, Matthew W.; Kuaprasert, Buabarn; McNae, Iain W.
  • Journal of Molecular Biology, Vol. 394, Issue 3
  • DOI: 10.1016/j.jmb.2009.09.041

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

Identifying sub-optimal responses to ivermectin in the treatment of River Blindness
journal, September 2009

  • Churcher, T. S.; Pion, S. D. S.; Osei-Atweneboana, M. Y.
  • Proceedings of the National Academy of Sciences, Vol. 106, Issue 39
  • DOI: 10.1073/pnas.0906176106

Phenotypic Evidence of Emerging Ivermectin Resistance in Onchocerca volvulus
journal, March 2011

  • Osei-Atweneboana, Mike Y.; Awadzi, Kwablah; Attah, Simon K.
  • PLoS Neglected Tropical Diseases, Vol. 5, Issue 3
  • DOI: 10.1371/journal.pntd.0000998

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

Molecular and biochemical characterization of nematode cofactor independent phosphoglycerate mutases
journal, December 2007


Mechanism of Catalysis of the Cofactor-independent Phosphoglycerate Mutase from Bacillus stearothermophilus: CRYSTAL STRUCTURE OF THE COMPLEX WITH 2-PHOSPHOGLYCERATE
journal, April 2000

  • Jedrzejas, Mark J.; Chander, Monica; Setlow, Peter
  • Journal of Biological Chemistry, Vol. 275, Issue 30
  • DOI: 10.1074/jbc.M002544200

How proteins bind macrocycles
journal, July 2014

  • Villar, Elizabeth A.; Beglov, Dmitri; Chennamadhavuni, Spandan
  • Nature Chemical Biology, Vol. 10, Issue 9
  • DOI: 10.1038/nchembio.1584

Cofactor-independent Phosphoglycerate Mutase Has an Essential Role in Caenorhabditis elegans and Is Conserved in Parasitic Nematodes
journal, July 2004

  • Zhang, Yinhua; Foster, Jeremy M.; Kumar, Sanjay
  • Journal of Biological Chemistry, Vol. 279, Issue 35
  • DOI: 10.1074/jbc.M405877200

XDS
journal, January 2010

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

mRNA display: from basic principles to macrocycle drug discovery
journal, April 2014


Structure and mechanism of action of a cofactor-dependent phosphoglycerate mutase homolog from Bacillus stearothermophilus with broad specificity phosphatase activity
journal, February 2002

  • Rigden, Daniel J.; Mello, Luciane V.; Setlow, Peter
  • Journal of Molecular Biology, Vol. 315, Issue 5
  • DOI: 10.1006/jmbi.2001.5290

A multisubstrate adduct inhibitor of a purine biosynthetic enzyme with a picomolar dissociation constant
journal, May 1989

  • Inglese, James; Blatchly, Richard A.; Benkovic, Stephen J.
  • Journal of Medicinal Chemistry, Vol. 32, Issue 5
  • DOI: 10.1021/jm00125a002

Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical libraries
journal, July 2006

  • Inglese, J.; Auld, D. S.; Jadhav, A.
  • Proceedings of the National Academy of Sciences, Vol. 103, Issue 31
  • DOI: 10.1073/pnas.0604348103

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

In vitro gene silencing of independent phosphoglycerate mutase (iPGM) in the filarial parasite Brugia malayi
journal, January 2013

  • Singh, Prashant Kumar; Kushwaha, Susheela; Mohd, Shahab
  • Infectious Diseases of Poverty, Vol. 2, Issue 1
  • DOI: 10.1186/2049-9957-2-5

Structural Basis for Potent Inhibition of SIRT2 Deacetylase by a Macrocyclic Peptide Inducing Dynamic Structural Change
journal, February 2014


Structural role of the active-site metal in the conformation of Trypanosoma brucei phosphoglycerate mutase: Structural role of the active-site metal
journal, April 2012


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

Thailandepsins: Bacterial Products with Potent Histone Deacetylase Inhibitory Activities and Broad-Spectrum Antiproliferative Activities
journal, October 2011

  • Wang, Cheng; Henkes, Leonhard M.; Doughty, Leah B.
  • Journal of Natural Products, Vol. 74, Issue 10
  • DOI: 10.1021/np200324x

Construction and screening of vast libraries of natural product-like macrocyclic peptides using in vitro display technologies
journal, February 2015


Discovery of Macrocyclic Peptides Armed with a Mechanism-Based Warhead: Isoform-Selective Inhibition of Human Deacetylase SIRT2
journal, February 2012

  • Morimoto, Jumpei; Hayashi, Yuuki; Suga, Hiroaki
  • Angewandte Chemie International Edition, Vol. 51, Issue 14
  • DOI: 10.1002/anie.201108118

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

Novel Inhibitors of Alkaline Phosphatase Suppress Vascular Smooth Muscle Cell Calcification
journal, July 2007

  • Narisawa, Sonoko; Harmey, Dympna; Yadav, Manisha C.
  • Journal of Bone and Mineral Research, Vol. 22, Issue 11
  • DOI: 10.1359/jbmr.070714

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

Complete catalytic cycle of cofactor-independent phosphoglycerate mutase involves a spring-loaded mechanism
journal, February 2015

  • Roychowdhury, Amlan; Kundu, Anirban; Bose, Madhuparna
  • The FEBS Journal, Vol. 282, Issue 6
  • DOI: 10.1111/febs.13205

Phosphoglycerate mutase from Trypanosoma brucei is hyperactivated by cobalt in vitro, but not in vivo
journal, January 2011

  • Fuad, Fazia Adyani Ahmad; Fothergill-Gilmore, Linda A.; Nowicki, Matthew W.
  • Metallomics, Vol. 3, Issue 12
  • DOI: 10.1039/c1mt00119a

Cofactor-Independent Phosphoglycerate Mutase from Nematodes Has Limited Druggability, as Revealed by Two High-Throughput Screens
journal, January 2014


Drugging Undruggable Molecular Cancer Targets
journal, January 2016


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


Zone Behavior of Enzymes
journal, July 1943

  • Straus, Oliver H.; Goldstein, Avram
  • The Journal of General Physiology, Vol. 26, Issue 6
  • DOI: 10.1085/jgp.26.6.559

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


Natural Product-Like Macrocyclic N-Methyl-Peptide Inhibitors against a Ubiquitin Ligase Uncovered from a Ribosome-Expressed De Novo Library
journal, December 2011


In Vitro Selection of Anti-Akt2 Thioether-Macrocyclic Peptides Leading to Isoform-Selective Inhibitors
journal, January 2012

  • Hayashi, Yuuki; Morimoto, Jumpei; Suga, Hiroaki
  • ACS Chemical Biology, Vol. 7, Issue 3
  • DOI: 10.1021/cb200388k

A Macrocyclic Peptide that Serves as a Cocrystallization Ligand and Inhibits the Function of a MATE Family Transporter
journal, August 2013


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

Mining Predicted Essential Genes of Brugia malayi for Nematode Drug Targets
journal, November 2007


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

Insights into the Catalytic Mechanism of Cofactor-independent Phosphoglycerate Mutase from X-ray Crystallography, Simulated Dynamics and Molecular Modeling
journal, May 2003


Nematode genome evolution
journal, January 2005


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    Ribosomal synthesis and folding of peptide-helical aromatic foldamer hybrids
    journal, March 2018


    Quantitative high-throughput screening assays for the discovery and development of SIRPα-CD47 interaction inhibitors
    journal, July 2019


    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

    • Hirose, Hisaaki; Hideshima, Tomoki; Katoh, Takayuki
    • ChemBioChem, Vol. 20, Issue 16
    • DOI: 10.1002/cbic.201900039

    Structural characterization, biochemical, inhibition and computational studies of Entamoeba histolytica phosphoglycerate mutase: finding hits for a new antiamoebic drug
    journal, May 2018

    • la Cruz, Artemisa Luévano-De; Sanabria-Chanaga, Elkin Eduardo; Yépez-Mulia, Lilián
    • Medicinal Chemistry Research, Vol. 27, Issue 6
    • DOI: 10.1007/s00044-018-2184-y

    Macrocyclic peptide-based inhibition and imaging of hepatocyte growth factor
    journal, May 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

    • Katoh, Takayuki; Suga, Hiroaki
    • International Journal of Molecular Sciences, Vol. 20, Issue 3
    • DOI: 10.3390/ijms20030522