Evidence, hypotheses and significance of MAP kinase TNNI3K interacting with its partners

Lai, Zhong-Fang

doi:10.5494/wjh.v2.i2.22

Cited by 3 publications

(2 citation statements)

References 24 publications

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“…TNNI3K is a cardiomyocyte-specific protein kinase with key roles in cardiac contractility, hypertrophic remodeling, and cardiac differentiation, and helps to repair cardiac injury by suppressing cTnI, which facilitates the maintenance of heartbeat rhythm and contractual force [23,24]. Mutations in TNNI3K have been linked to numerous cardiac phenotypes including cardiac conduction, atrial/junctional tachycardia, dilated cardiomyopathy, and heart failure [16,[25][26][27].…”

Section: Introductionmentioning

confidence: 99%

A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family

Ramzan

Tennstedt

Tariq

et al. 2021

Genes

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Cardiac conduction disease (CCD), which causes altered electrical impulse propagation in the heart, is a life-threatening condition with high morbidity and mortality. It exhibits genetic and clinical heterogeneity with diverse pathomechanisms, but in most cases, it disrupts the synchronous activity of impulse-generating nodes and impulse-conduction underlying the normal heartbeat. In this study, we investigated a consanguineous Pakistani family comprised of four patients with CCD. We applied whole exome sequencing (WES) and co-segregation analysis, which identified a novel homozygous missense mutation (c.1531T>C;(p.Ser511Pro)) in the highly conserved kinase domain of the cardiac troponin I-interacting kinase (TNNI3K) encoding gene. The behaviors of mutant and native TNNI3K were compared by performing all-atom long-term molecular dynamics simulations, which revealed changes at the protein surface and in the hydrogen bond network. Furthermore, intra and intermolecular interaction analyses revealed that p.Ser511Pro causes structural variation in the ATP-binding pocket and the homodimer interface. These findings suggest p.Ser511Pro to be a pathogenic variant. Our study provides insights into how the variant perturbs the TNNI3K structure-function relationship, leading to a disease state. This is the first report of a recessive mutation in TNNI3K and the first mutation in this gene identified in the Pakistani population.

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Section: Introductionmentioning

confidence: 99%

A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family

Ramzan

Tennstedt

Tariq

et al. 2021

Genes

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“…In mice, Tnni3k is shown to play an important role in the regulation of cardiac differentiation and cardiac contractility [5]. Overexpression of Tnni3k accelerated disease progression in mouse models of cardiomyopathy [6].…”

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confidence: 99%

Whole exome sequencing identifies the TNNI3K gene as a cause of familial conduction system disease and congenital junctional ectopic tachycardia

Honeywell

Zhang

et al. 2015

International Journal of Cardiology

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3D-QSAR Assisted Design of Novel 7-Deazapurine Derivatives as TNNI3K Kinase Inhibitors Using Molecular Docking and Molecular Dynamics Simulation

Balasubramanian

Balupuri

Bhujbal

et al. 2020

LDDD

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Background: Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific kinase that belongs to MAPKKK family. It is a dual-function kinase with tyrosine and serine/threonine kinase activity. Over-expression of TNNI3K results in various cardiovascular diseases such as cardiomyopathy, ischemia/reperfusion injury, heart failure, etc. Since, it is a cardiac-specific kinase and expressed only in heart tissue, it is an ideal molecular target to treat cardiac diseases. The main objective of the work is to study and understand the structure-activity relationship of the reported deazapurine derivatives and to use the 3D-QSAR and docking results to design potent and novel TNNI3K inhibitors of this series. Methods: In the present study, we have used molecular docking 3D QSAR, and molecular dynamics simulation to understand the structure-activity correlation of reported TNNI3K inhibitors and to design novel compounds of deazapurine derivatives with increased activity. Results: Both CoMFA (q2=0.669, NOC=5, r2=0.944) and CoMSIA (q2=0.783, NOC=5, r2=0.965) have resulted in satisfactory models. The models were validated using external test set, Leave-out- Five, bootstrapping, progressive scrambling, and rm2 metrics calculations. The validation procedures showed the developed models were robust and reliable. The docking results and the contour maps analysis helped in the better understanding of the structure-activity relationship. Conclusion: This is the first report on 3D-QSAR modeling studies of TNNI3K inhibitors. Both docking and MD results were consistent and showed good correlation with the previous experimental data. Based on the information obtained from contour maps, 31 novel TNNI3K inhibitors were designed. These designed compounds showed higher activity than the existing dataset compounds.

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Evidence, hypotheses and significance of MAP kinase TNNI3K interacting with its partners

Cited by 3 publications

References 24 publications

A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family

A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family

Whole exome sequencing identifies the TNNI3K gene as a cause of familial conduction system disease and congenital junctional ectopic tachycardia

3D-QSAR Assisted Design of Novel 7-Deazapurine Derivatives as TNNI3K Kinase Inhibitors Using Molecular Docking and Molecular Dynamics Simulation

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