Molecular modelling of the emergence of azole resistance in Mycosphaerella graminicola.
Molecular modelling of the emergence of azole resistance in Mycosphaerella graminicola.
复制标题
DOI：
10.1371/journal.pone.0020973
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Kelly SL
中科院分区：
文献类型：
--
作者：
Mullins JG;Parker JE;Cools HJ;Togawa RC;Lucas JA;Fraaije BA;Kelly DE;Kelly SL
最近出现的唑类（咪唑和三唑）抗性与小麦病原体禾生球腔菌CYP 51突变的结构原理，获得野生型蛋白质和13种变异蛋白质的同源性建模。新的M.禾生菌CYP 51是基于多个同源物，单独确定的每一个变体，而不是使用一个单一的结构支架，提供了一个强大的结构-功能原理的唑类化合物的结合，包括重要的真菌特异性区域，其中没有结构信息。野生型结合口袋揭示了与结合的唑类分子非常接近的特异性残基，所述唑类分子在变体中发生改变。这暗示唑类配体作为重要的试剂对与口袋接壤的特定区域施加选择，这成为遗传突变事件的焦点，导致对该组相关化合物的敏感性降低。总的来说，该模型解释了几个观察到的功能效应的具体改变，包括损失的三唑醇敏感性的Y137 F的变种，较低的敏感性戊唑醇的I381 V的变种和增加抗性咪鲜胺的V136 A的变种。Y 459和G460的缺失导致β转角的整个部分从结合口袋附近移除，赋予对戊唑醇和氟环唑的抗性，但在携带A379 G I381 V Δ Y 459/G460组合的变体中对咪鲜胺敏感。事实证明，结合口袋体积的测量对于评估对唑类药物的一般耐药性范围是有用的，因为它们具有调节作用，没有键合相互作用，特别是当结合关键氨基酸位置变化的分析时。有可能预测任何变体CYP中唑类分子的可能结合方向，从而为计算机筛选系统和可靠的预测方法提供潜力，以评估特定变体对特定唑类杀真菌剂表现出抗性的概率。
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 protein and 13 variant proteins. The novel molecular models of M. graminicola 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.
登录
查看更多内容
影响因子：
14.9
作者：
Eswar, N;John, B;Sali, A
通讯作者：
Sali, A
影响因子：
2.1
作者：
Lamb, DC;Kelly, DE;Kelly, SL
通讯作者：
Kelly, SL
影响因子：
2.9
作者：
BOSCOTT, PE;GRANT, GH
通讯作者：
GRANT, GH
影响因子：
4.1
作者：
Canas-Gutierrez, Gloria P.;Angarita-Velasquez, Monica J.;Arango, Rafael
通讯作者：
Arango, Rafael
影响因子：
3.5
作者：
Delye, C;Laigret, F;CorioCostet, MF
通讯作者：
CorioCostet, MF