Evaluation of CDK6 and p16/INK4a-Derived Peptides Interaction

Kazennov, Andrey; Alekseenko, Andrey; Боженко, В К; Kulinich, Tatiana; Shuvalov, Nikolay; Kholodov, Yaroslav

doi:10.4236/cmb.2013.33007

Cited by 3 publications

(3 citation statements)

References 20 publications

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“…To map the free energy landscape for unfolding of the WWdomain and a-peptide, we utilized the Umbrella Sampling technique (Supporting Information), [43] which is widely used to access the thermodynamics of biomolecules. [44][45][46] Using Umbrella Sampling requires generation and subsequent equilibration of initial conformations (windows), which span the entire range of reaction coordinate (elongation X). The potential of mean force was constructed using the Weighted Histogram Analysis Method.…”

Section: Umbrella Sampling Simulationsmentioning

confidence: 99%

SOP‐GPU: influence of solvent‐induced hydrodynamic interactions on dynamic structural transitions in protein assemblies

et al. 2016

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Hydrodynamic interactions (HI) are incorporated into Langevin dynamics of the Cα‐based protein model using the Truncated Expansion approximation (TEA) to the Rotne–Prager–Yamakawa diffusion tensor. Computational performance of the obtained GPU realization demonstrates the model's capability for describing protein systems of varying complexity (102–105 residues), including biological particles (filaments, virus shells). Comparison of numerical accuracy of the TEA versus exact description of HI reveals similar results for the kinetics and thermodynamics of protein unfolding. The HI speed up and couple biomolecular transitions through cross‐communication among protein domains, which result in more collective displacements of structure elements governed by more deterministic (less variable) dynamics. The force‐extension/deformation spectra from nanomanipulations in silico exhibit sharper force signals that match well the experimental profiles. Hence, biomolecular simulations without HI overestimate the role of tension/stress fluctuations. Our findings establish the importance of incorporating implicit water‐mediated many‐body effects into theoretical modeling of dynamic processes involving biomolecules. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.

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Section: Umbrella Sampling Simulationsmentioning

confidence: 99%

SOP‐GPU: influence of solvent‐induced hydrodynamic interactions on dynamic structural transitions in protein assemblies

et al. 2016

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“…Однако большинство CDKs представляют собой трудно уязвимую терапевтическую мишень в силу своих структурных особенностей [10,11]. Ранее нами была разработана стратегия, объединяющая методы компьютерного моделирования, белкового докинга и молекулярной динамики, направленная на поиск биологически активных пептидных конструкций, в частности ингибиторов CDK4 / 6 [12,13].…”

Section: Introductionunclassified

Study of cytostatic and cytotoxic characteristics of modified peptide CDK4/6 inhibitors – functional analogs of p16INK4a (90-97)

et al. 2021

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Background. Application of mathematical modeling for search for biologically active molecules is currently a promising scientific approach. Application of numerical algorithms for optimization of peptide sequences and molecular dynamics allowed to obtain modified peptide sequences that are functional analogs of the sequence of natural inhibitor of cyclin-dependent kinase 4/6 p16INK4a.The study objective is to establish biological characteristics of peptide sequences of CDK 4/6 inhibitors obtained using mathematical modeling.Materials and methods. The studies were performed in vitro using tumor cell lines (MCF-7, А549, SKOV-3, НСТ116). Apoptosis level, cell distribution per cell cycle stages, changes in Bcl-2 expression, changes in the level of phosphorylated pRb under the effect of the studied molecules were investigated using flow cytometry. Proliferation dynamics of cell populations were studied using RTCA iCELLIgence biosensor technology.Results. Peptide sequences obtained using mathematical modeling decrease the level of phosphorylated pRb, Bcl-2 expression when applied to actively proliferating cells. These proteins serve as molecular targets for the cyclin-dependent kinase 4/6–cyclin D complex, and changes in pRb and Bcl-2 levels might indicate inhibition of complex formation. Consequently, decreased proliferative activity and increased apoptosis were observed. Effectiveness of the peptide sequences depended on their molecular structure and type of the used cell line. Two (2) of the studied modified peptide sequences have higher antiproliferative and proapoptotic effect on tumor cells than native p16INK4a (90-97) sequence.Conclusion. Application of mathematical modeling for search and development of functionally active molecules allowed to create peptide sequences with stronger cyclin-dependent kinase inhibitor effect than p16INK4a, the native inhibitor CDK4/6.

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“…These two proteins are unrelated in sequence and are expressed from two different promoters, which give rise to two alternative transcripts. INK4A inhibits specifically the cyclin D dependent kinases 4 and 6 (Fahham, Ghahremani, Sardari, Vaziri, & Ostad, 2009;Kazennov et al, 2013) through binding to these proteins, thereby preventing them from forming productive complexes with cyclin D. In consequence, phosphorylation of the retinoblastoma protein RB that is necessary for cell cycle progression cannot occur (Duronio & Xiong, 2013). ARF inhibits the degradation of the cell cycle regulator p53 by forming a stable complex with the ubiquitin ligase MDM2 in the nucleus (Sperka, Wang, & Rudolph, 2012).…”

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Analysis of the putative tumor suppressor gene cdkn2ab in pigment cells and melanoma of Xiphophorus and medaka

Regneri

Klotz

Wilde

et al. 2018

Pigment Cell Melanoma Res

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In humans, the CDKN2A locus encodes two transcripts, INK4A and ARF. Inactivation of either one by mutations or epigenetic changes is a frequent signature of malignant melanoma and one of the most relevant entry points for melanomagenesis. To analyze whether cdkn2ab, the fish ortholog of CDKN2A, has a similar function as its human counterpart, we studied its action in fish models for human melanoma. Overexpression of cdkn2ab in a Xiphophorus melanoma cell line led to decreased proliferation and induction of a senescence-like phenotype, indicating a melanoma-suppressive function analogous to mammals. Coexpression of Xiphophorus cdkn2ab in medaka transgenic for the mitfa:xmrk melanoma-inducing gene resulted in full suppression of melanoma development, whereas CRISPR/Cas9 knockout of cdkn2ab resulted in strongly enhanced tumor growth. In summary, this provides the first functional evidence that cdkn2ab acts as a potent tumor suppressor gene in fish melanoma models.

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Evaluation of CDK6 and p16/INK4a-Derived Peptides Interaction

Cited by 3 publications

References 20 publications

SOP‐GPU: influence of solvent‐induced hydrodynamic interactions on dynamic structural transitions in protein assemblies

SOP‐GPU: influence of solvent‐induced hydrodynamic interactions on dynamic structural transitions in protein assemblies

Study of cytostatic and cytotoxic characteristics of modified peptide CDK4/6 inhibitors – functional analogs of p16INK4a (90-97)

Analysis of the putative tumor suppressor gene cdkn2ab in pigment cells and melanoma of Xiphophorus and medaka

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