Impact of amino acid substitution in the kinase domain of Bruton tyrosine kinase and its association with X-linked agammaglobulinemia

Amir, Mohd.; Prasad, Kartikay; Batra, Sagar; Kumar, Vijay; Hussain, Afzal; Rehman, Tabish; Alajmi, Mohamed F.; Hassan, Md. Imtaiyaz

doi:10.1016/j.ijbiomac.2020.08.057

Cited by 24 publications

(14 citation statements)

References 63 publications

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“…If a mutation is shown destabilizing by four out of the five tools, we have considered that as a destabilizing mutation. A detailed protocol of structure-based mutational analyses can be found in our previous reports ( Amir et al., 2019 ; Mohammad et al., 2020 ; Choudhury et al., 2021 ; Habib et al., 2021 ; Umair et al., 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Genomic Variations in the Structural Proteins of SARS-CoV-2 and Their Deleterious Impact on Pathogenesis: A Comparative Genomics Approach

Mohammad

Choudhury

Habib

et al. 2021

Front. Cell. Infect. Microbiol.

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A continual rise in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causing coronavirus disease (COVID-19) has become a global threat. The main problem comes when SARS-CoV-2 gets mutated with the rising infection and becomes more lethal for humankind than ever. Mutations in the structural proteins of SARS-CoV-2, i.e., the spike surface glycoprotein (S), envelope (E), membrane (M) and nucleocapsid (N), and replication machinery enzymes, i.e., main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) creating more complexities towards pathogenesis and the available COVID-19 therapeutic strategies. This study analyzes how a minimal variation in these enzymes, especially in S protein at the genomic/proteomic level, affects pathogenesis. The structural variations are discussed in light of the failure of small molecule development in COVID-19 therapeutic strategies. We have performed in-depth sequence- and structure-based analyses of these proteins to get deeper insights into the mechanism of pathogenesis, structure-function relationships, and development of modern therapeutic approaches. Structural and functional consequences of the selected mutations on these proteins and their association with SARS-CoV-2 virulency and human health are discussed in detail in the light of our comparative genomics analysis.

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Section: Methodsmentioning

confidence: 99%

Genomic Variations in the Structural Proteins of SARS-CoV-2 and Their Deleterious Impact on Pathogenesis: A Comparative Genomics Approach

Mohammad

Choudhury

Habib

et al. 2021

Front. Cell. Infect. Microbiol.

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“…The MD simulations were further employed to explore an in‐depth analysis of structural stability which is correlated with the atomic compactness around the coordinates of protein 45,46 . The radius of gyration (Rg) is a measure of arranged and bounded atoms along the axis, an inter‐atomically bounded conformation leads to the generation of Rg and corresponding stability, that is, a higher value of Rg for a protein indicates a significant stable structure 36 .…”

Section: Resultsmentioning

confidence: 99%

Exploring insights of syntaxin superfamily proteins from Entamoeba histolytica: a prospective simulation, protein‐protein interaction, and docking study

Batra

Pancholi

Roy

et al. 2021

J of Molecular Recognition

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Entamoeba histolytica (Eh), a parasitic protozoan and the causative agent of invasive Amoebiasis, invade the host tissue through an effective secretory pathway. There are several lines of evidence suggesting that amoebic trophozoite pore‐forming complex amoebapore and a large class of proteases enzymes including rhomboid proteases, cysteine proteases, and metalloproteases are implicated in host tissue invasion. For successful delivery of these molecules/cargos, trophozoites heavily rely on sorting machinery from the endoplasmic reticulum, Golgi to plasma membrane. Although, sole secretion machinery in E. histolytica is not characterized yet. Therefore, here our aim is to understand the properties of key molecules N‐ethylmaleimide‐sensitive fusion protein attached to protein receptors (SNAREs) in E. histolytica. SNAREs proteins are an important component of the membrane‐trafficking machinery and have been associated in a range of processes including vesicle tethering, fusion as well as specificity of vesicular transport in all eukaryotic cells. SNARE proteins are architecturally simple, categorized by the presence of one copy of a homologous coiled‐coil forming motif. However, the structural information and protein‐protein interaction study of Eh‐associated syntaxin proteins are still not known. Here, we characterize the syntaxin 1 like molecule and VAMP from Eh through physiochemical profiling, modeling, atomistic simulation, protein‐protein interaction, and docking approaches on the proteins containing SNARE and synaptobrevin domain. The modeled structures and the critical residues recognized through protein interaction and docking study may provide better structural and functional insights into these proteins and may aid in the development of newer diagnostic assays.

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“…To investigate the impact of induced mutations on each amino acid residue of TBK1, [84][85][86] the intensive movements in TBK1-WT, TBK1-K38D, and TBK1-S172A mutant systems were measured using PCA constructed on the eigenvector. The scattered plot in Figure 8A fundamentally provides a two-dimensional illustration of the conformational modifications occupied by the systems.…”

Section: Principal Component Analysismentioning

confidence: 99%

Impact of single amino acid substitution on the structure and function of TANK‐binding kinase‐1

Umair

Khan

Shafie

et al. 2021

J of Cellular Biochemistry

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Tank-binding kinase 1 (TBK1) is a serine/threonine protein kinase involved in various signaling pathways and subsequently regulates cell proliferation, apoptosis, autophagy, antiviral and antitumor immunity. Dysfunction of TBK1 can cause many complex diseases, including autoimmunity, neurodegeneration, and cancer. This dysfunction of TBK1 may result from single amino acid substitutions and subsequent structural alterations. This study analyzed the effect of substituting amino acids on TBK1 structure, function, and subsequent disease using advanced computational methods and various tools. In the initial assessment, a total of 467 mutations were found to be deleterious. After that, in detailed structural and sequential analyses, 13 mutations were found to be pathogenic. Finally, based on the functional importance, two variants (K38D and S172A) of the TBK1 kinase domain were selected and studied in detail by utilizing all-atom molecular dynamics (MD) simulation for 200 ns. MD simulation, including correlation matrix and principal component analysis, helps to get deeper insights into the TBK1 structure at the atomic level. We observed a substantial change in variants' conformation, which may be possible for structural alteration and subsequent TBK1 dysfunction. However, substitution S172A shows a significant conformational change in TBK1 structure as compared to K38D. Thus, this study provides a structural basis to understand the effect of mutations on the kinase domain of TBK1 and its function associated with disease progression.

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Impact of amino acid substitution in the kinase domain of Bruton tyrosine kinase and its association with X-linked agammaglobulinemia

Cited by 24 publications

References 63 publications

Genomic Variations in the Structural Proteins of SARS-CoV-2 and Their Deleterious Impact on Pathogenesis: A Comparative Genomics Approach

Genomic Variations in the Structural Proteins of SARS-CoV-2 and Their Deleterious Impact on Pathogenesis: A Comparative Genomics Approach

Exploring insights of syntaxin superfamily proteins from Entamoeba histolytica: a prospective simulation, protein‐protein interaction, and docking study

Impact of single amino acid substitution on the structure and function of TANK‐binding kinase‐1

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