Molecular Modelling of the Emergence of Azole Resistance in Mycosphaerella graminicola

Mullins, Jonathan; Parker, Josie; Cools, Hans J.; Togawa, Roberto C.; Lucas, John A.; Fraaije, Bart A.; Kelly, Diane; Kelly, Steven

doi:10.1371/journal.pone.0020973

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Molecular Modelling of the Emergence of Azole Resistance in Mycosphaerella graminicola

Jonathan Mullins

, Josie Parker, Hans J. Cools, Roberto C. Togawa, John A. Lucas, Bart A. Fraaije, Diane Kelly, Steven Kelly

PLoS ONE, Volume: 6, Issue: 6, Start page: e20973

Swansea University Authors: Jonathan Mullins , Josie Parker, Diane Kelly, Steven Kelly

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DOI (Published version): 10.1371/journal.pone.0020973

Abstract

A structural rationale for recent emergence of azole (imidazole and triazole) resistance associated with CYP51 mutations in the wheat pathogen Mycosphaerella graminicola is presented, attained by homology modelling of the wild type p...

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Published in:	PLoS ONE
ISSN:	1932-6203
Published:	2011
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URI:	https://cronfa.swan.ac.uk/Record/cronfa6839
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first_indexed	2013-07-23T11:55:34Z
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The novel molecular models of </span><em>M. graminicola</em><span> CYP51 are based on multiple homologues, individually identified for each variant, rather than using a single structural scaffold, providing a robust structure-function rationale for the binding of azoles, including important fungal specific regions for which no structural information is available. The wild type binding pocket reveals specific residues in close proximity to the bound azole molecules that are subject to alteration in the variants. This implicates azole ligands as important agents exerting selection on specific regions bordering the pocket, that become the focus of genetic mutation events, leading to reduced sensitivity to that group of related compounds. Collectively, the models account for several observed functional effects of specific alterations, including loss of triadimenol sensitivity in the Y137F variant, lower sensitivity to tebuconazole of I381V variants and increased resistance to prochloraz of V136A variants. Deletion of Y459 and G460, which brings about removal of that entire section of beta turn from the vicinity of the binding pocket, confers resistance to tebuconazole and epoxiconazole, but sensitivity to prochloraz in variants carrying a combination of A379G I381V ΔY459/G460. Measurements of binding pocket volume proved useful in assessment of scope for general resistance to azoles by virtue of their accommodation without bonding interaction, particularly when combined with analysis of change in positions of key amino acids. It is possible to predict the likely binding orientation of an azole molecule in any of the variant CYPs, providing potential for an in silico screening system and reliable predictive approach to assess the probability of particular variants exhibiting resistance to particular azole fungicides.</span></p></abstract><type>Journal Article</type><journal>PLoS ONE</journal><volume>6</volume><journalNumber>6</journalNumber><paginationStart>e20973</paginationStart><publisher/><issnElectronic>1932-6203</issnElectronic><keywords/><publishedDay>27</publishedDay><publishedMonth>6</publishedMonth><publishedYear>2011</publishedYear><publishedDate>2011-06-27</publishedDate><doi>10.1371/journal.pone.0020973</doi><url/><notes></notes><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm/><lastEdited>2019-07-01T15:42:16.6096353</lastEdited><Created>2012-01-25T14:31:53.6870000</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Jonathan</firstname><surname>Mullins</surname><orcid>0000-0003-0144-2962</orcid><order>1</order></author><author><firstname>Josie</firstname><surname>Parker</surname><order>2</order></author><author><firstname>Hans J.</firstname><surname>Cools</surname><order>3</order></author><author><firstname>Roberto C.</firstname><surname>Togawa</surname><order>4</order></author><author><firstname>John A.</firstname><surname>Lucas</surname><order>5</order></author><author><firstname>Bart A.</firstname><surname>Fraaije</surname><order>6</order></author><author><firstname>Diane</firstname><surname>Kelly</surname><order>7</order></author><author><firstname>Steven</firstname><surname>Kelly</surname><orcid>0000-0001-7991-5040</orcid><order>8</order></author></authors><documents/><OutputDurs/></rfc1807>
spelling	2019-07-01T15:42:16.6096353 v2 6839 2012-01-25 Molecular Modelling of the Emergence of Azole Resistance in Mycosphaerella graminicola 4cf2dddedbe1dacb506ec925fdbd5b40 0000-0003-0144-2962 Jonathan Mullins Jonathan Mullins true false e563ed4e1c7db8d1e131fb78a5f8d0d5 Josie Parker Josie Parker true false 5ccf81e5d5beedf32ef8d7c3d7ac6c8c Diane Kelly Diane Kelly true false b17cebaf09b4d737b9378a3581e3de93 0000-0001-7991-5040 Steven Kelly Steven Kelly true false 2012-01-25 BMS <p><span>A structural rationale for recent emergence of azole (imidazole and triazole) resistance associated with CYP51 mutations in the wheat pathogen </span><em>Mycosphaerella graminicola</em><span> is presented, attained by homology modelling of the wild type protein and 13 variant proteins. The novel molecular models of </span><em>M. graminicola</em><span> CYP51 are based on multiple homologues, individually identified for each variant, rather than using a single structural scaffold, providing a robust structure-function rationale for the binding of azoles, including important fungal specific regions for which no structural information is available. The wild type binding pocket reveals specific residues in close proximity to the bound azole molecules that are subject to alteration in the variants. This implicates azole ligands as important agents exerting selection on specific regions bordering the pocket, that become the focus of genetic mutation events, leading to reduced sensitivity to that group of related compounds. Collectively, the models account for several observed functional effects of specific alterations, including loss of triadimenol sensitivity in the Y137F variant, lower sensitivity to tebuconazole of I381V variants and increased resistance to prochloraz of V136A variants. Deletion of Y459 and G460, which brings about removal of that entire section of beta turn from the vicinity of the binding pocket, confers resistance to tebuconazole and epoxiconazole, but sensitivity to prochloraz in variants carrying a combination of A379G I381V ΔY459/G460. Measurements of binding pocket volume proved useful in assessment of scope for general resistance to azoles by virtue of their accommodation without bonding interaction, particularly when combined with analysis of change in positions of key amino acids. It is possible to predict the likely binding orientation of an azole molecule in any of the variant CYPs, providing potential for an in silico screening system and reliable predictive approach to assess the probability of particular variants exhibiting resistance to particular azole fungicides.</span></p> Journal Article PLoS ONE 6 6 e20973 1932-6203 27 6 2011 2011-06-27 10.1371/journal.pone.0020973 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2019-07-01T15:42:16.6096353 2012-01-25T14:31:53.6870000 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Jonathan Mullins 0000-0003-0144-2962 1 Josie Parker 2 Hans J. Cools 3 Roberto C. Togawa 4 John A. Lucas 5 Bart A. Fraaije 6 Diane Kelly 7 Steven Kelly 0000-0001-7991-5040 8
title	Molecular Modelling of the Emergence of Azole Resistance in Mycosphaerella graminicola
spellingShingle	Molecular Modelling of the Emergence of Azole Resistance in Mycosphaerella graminicola Jonathan Mullins Josie Parker Diane Kelly Steven Kelly
title_short	Molecular Modelling of the Emergence of Azole Resistance in Mycosphaerella graminicola
title_full	Molecular Modelling of the Emergence of Azole Resistance in Mycosphaerella graminicola
title_fullStr	Molecular Modelling of the Emergence of Azole Resistance in Mycosphaerella graminicola
title_full_unstemmed	Molecular Modelling of the Emergence of Azole Resistance in Mycosphaerella graminicola
title_sort	Molecular Modelling of the Emergence of Azole Resistance in Mycosphaerella graminicola
author_id_str_mv	4cf2dddedbe1dacb506ec925fdbd5b40 e563ed4e1c7db8d1e131fb78a5f8d0d5 5ccf81e5d5beedf32ef8d7c3d7ac6c8c b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv	4cf2dddedbe1dacb506ec925fdbd5b40_*_Jonathan Mullins e563ed4e1c7db8d1e131fb78a5f8d0d5__Josie Parker 5ccf81e5d5beedf32ef8d7c3d7ac6c8c__Diane Kelly b17cebaf09b4d737b9378a3581e3de93_*_Steven Kelly
author	Jonathan Mullins Josie Parker Diane Kelly Steven Kelly
author2	Jonathan Mullins Josie Parker Hans J. Cools Roberto C. Togawa John A. Lucas Bart A. Fraaije Diane Kelly Steven Kelly
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container_title	PLoS ONE
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container_issue	6
container_start_page	e20973
publishDate	2011
institution	Swansea University
issn	1932-6203
doi_str_mv	10.1371/journal.pone.0020973
college_str	Faculty of Medicine, Health and Life Sciences
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department_str	Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description	<p><span>A structural rationale for recent emergence of azole (imidazole and triazole) resistance associated with CYP51 mutations in the wheat pathogen </span><em>Mycosphaerella graminicola</em><span> is presented, attained by homology modelling of the wild type protein and 13 variant proteins. The novel molecular models of </span><em>M. graminicola</em><span> CYP51 are based on multiple homologues, individually identified for each variant, rather than using a single structural scaffold, providing a robust structure-function rationale for the binding of azoles, including important fungal specific regions for which no structural information is available. The wild type binding pocket reveals specific residues in close proximity to the bound azole molecules that are subject to alteration in the variants. This implicates azole ligands as important agents exerting selection on specific regions bordering the pocket, that become the focus of genetic mutation events, leading to reduced sensitivity to that group of related compounds. Collectively, the models account for several observed functional effects of specific alterations, including loss of triadimenol sensitivity in the Y137F variant, lower sensitivity to tebuconazole of I381V variants and increased resistance to prochloraz of V136A variants. Deletion of Y459 and G460, which brings about removal of that entire section of beta turn from the vicinity of the binding pocket, confers resistance to tebuconazole and epoxiconazole, but sensitivity to prochloraz in variants carrying a combination of A379G I381V ΔY459/G460. Measurements of binding pocket volume proved useful in assessment of scope for general resistance to azoles by virtue of their accommodation without bonding interaction, particularly when combined with analysis of change in positions of key amino acids. It is possible to predict the likely binding orientation of an azole molecule in any of the variant CYPs, providing potential for an in silico screening system and reliable predictive approach to assess the probability of particular variants exhibiting resistance to particular azole fungicides.</span></p>
published_date	2011-06-27T03:08:26Z
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score	11.016235

Molecular Modelling of the Emergence of Azole Resistance in Mycosphaerella graminicola

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