白细胞介素-1受体相关激酶4(IRAK4)在toll样受体(TLR)信号通路中具有重要作用,这种分子的功能障碍除了癌症之外,还可能导致各种感染和免疫相关的疾病。IRAK4基因变异与各种类型的疾病有关。因此,我们进行了全面的分析,以识别对IRAK4最具破坏性影响的错义变体,并采用不同的生物信息学工具来研究单核苷酸多态性对功能的影响,稳定性,二级结构,和3D结构。还研究了残基在蛋白质结构域上的位置及其保守状态。此外,对接工具和结构生物学参与分析SNP对一种已开发的IRAK4抑制剂的影响。通过分析IRAK4基因SNPs,分析将十个变体区分为最有害的错义变体。所有变体位于重要蛋白质结构域上的高度保守位置。L318S和L318F突变与IRAK4二级结构的变化有关。通过I-Mutant2.0和Mu-Pro工具,发现八个SNP对IRAK4的稳定性具有降低的作用,而Mu-Pro工具确定了G198ESNP的降低效应。此外,还发现了所选变体对IRAK4的3D结构的不利影响。分子建模研究强调了这些鉴定的SNP突变残基对IRAK4ATP结合位点对已知靶抑制剂的成药性的有害影响。HG-12-6,与天然蛋白质相比。失去重要的配体残基接触,改变蛋白质的整体灵活性,增加的空间碰撞,甚至在配体结合位点界面处的电子惩罚都被认为与SNP模型有关,以阻碍HG-12-6对IRAK4靶蛋白的亲和力。该给定模型为更好地预测与IRAK4故障相关的各种疾病奠定了基础,并阐明了有害的IRAK4变体对IRAK4抑制剂功效的影响。
Interleukin-1-receptor-associated kinase 4 (IRAK4) possesses a crucial function in the toll-like receptor (TLR) signaling pathway, and the dysfunction of this molecule could lead to various infectious and immune-related diseases in addition to cancers. IRAK4 genetic variants have been linked to various types of diseases. Therefore, we conducted a comprehensive analysis to recognize the missense variants with the most damaging impacts on IRAK4 with the employment of diverse bioinformatics tools to study single-nucleotide polymorphisms\' effects on function, stability, secondary structures, and 3D structure. The residues\' location on the protein domain and their conservation status were investigated as well. Moreover, docking tools along with structural biology were engaged in analyzing the SNPs\' effects on one of the developed IRAK4 inhibitors. By analyzing IRAK4 gene SNPs, the analysis distinguished ten variants as the most detrimental missense variants. All variants were situated in highly conserved positions on an important protein domain. L318S and L318F mutations were linked to changes in IRAK4 secondary structures. Eight SNPs were revealed to have a decreasing effect on the stability of IRAK4 via both I-Mutant 2.0 and Mu-Pro tools, while Mu-Pro tool identified a decreasing effect for the G198E SNP. In addition, detrimental effects on the 3D structure of IRAK4 were also discovered for the selected variants. Molecular modeling studies highlighted the detrimental impact of these identified SNP mutant residues on the druggability of the IRAK4 ATP-binding site towards the known target inhibitor, HG-12-6, as compared to the native protein. The loss of important ligand residue-wise contacts, altered protein global flexibility, increased steric clashes, and even electronic penalties at the ligand-binding site interfaces were all suggested to be associated with SNP models for hampering the HG-12-6 affinity towards IRAK4 target protein. This given model lays the foundation for the better prediction of various disorders relevant to IRAK4 malfunction and sheds light on the impact of deleterious IRAK4 variants on IRAK4 inhibitor efficacy.