The Experts below are selected from a list of 292197 Experts worldwide ranked by ideXlab platform
Jans Alzate-morales - One of the best experts on this subject based on the ideXlab platform.
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Mechanistic insights into the phosphoryl transfer reaction in Cyclin-Dependent Kinase 2: A QM/MM study.
PloS one, 2019Co-Authors: Rodrigo Recabarren, Edison Osorio, Julio Caballero, Iñaki Tuñón, Jans Alzate-moralesAbstract:Cyclin-Dependent Kinase 2 (CDK2) is an important member of the CDK family exerting its most important function in the regulation of the cell cycle. It catalyzes the transfer of the gamma phosphate group from an ATP (adenosine triphosphate) molecule to a Serine/Threonine residue of a peptide substrate. Due to the importance of this enzyme, and protein Kinases in general, a detailed understanding of the reaction mechanism is desired. Thus, in this work the phosphoryl transfer reaction catalyzed by CDK2 was revisited and studied by means of hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. Our results suggest that the base-assisted mechanism is preferred over the substrate-assisted pathway when one Mg2+ is present in the active site, in agreement with a previous theoretical study. The base-assisted mechanism resulted to be dissociative, with a potential energy barrier of 14.3 kcal/mol, very close to the experimental derived value. An interesting feature of the mechanism is the proton transfer from Lys129 to the phosphoryl group at the second transition state, event that could be helping in neutralizing the charge on the phosphoryl group upon the absence of a second Mg2+ ion. Furthermore, important insights into the mechanisms in terms of bond order and charge analysis were provided. These descriptors helped to characterize the synchronicity of bond forming and breaking events, and to characterize charge transfer effects. Local interactions at the active site are key to modulate the charge distribution on the phosphoryl group and therefore alter its reactivity.
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Mechanistic insights into the phosphoryl transfer reaction in Cyclin-Dependent Kinase 2: a QM/MM study
2019Co-Authors: Rodrigo Recabarren, Edison Osorio, Julio Caballero, Iñaki Tuñón, Jans Alzate-moralesAbstract:Abstract Cyclin-Dependent Kinase 2 (CDK2) is an important member of the CDK family exerting its most important function in the regulation of the cell cycle. It catalyzes the transfer of the gamma phosphate group from an ATP (adenosine triphosphate) molecule to a Serine/Threonine residue of a peptide substrate. Due to the importance of this enzyme, and protein Kinases in general, a detailed understanding of the reaction mechanism is desired. Thus, in this work the phosphoryl transfer reaction catalyzed by CDK2 was revisited and studied by means of hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. Our results show that the base-assisted mechanism is preferred over the substrate-assisted pathway, in agreement with a previous theoretical study. The base-assisted mechanism resulted to be dissociative, with a potential energy barrier of 14.3 kcal/mol, very close to the experimental derived value. An interesting feature of the mechanism is the proton transfer from Lys129 to the phosphoryl group at the second transition state, event that could be helping in neutralizing the charge on the phosphoryl group upon the absence of a second Mg2+ ion. Furthermore, important insights into the mechanisms in terms of bond order and charge analysis were provided. These descriptors helped to characterize the synchronicity of bond forming and breaking events, and to characterize charge transfer effects. Local interactions at the active site are key to modulate the charge distribution on the phosphoryl group and therefore alter its reactivity.
Rob Howes - One of the best experts on this subject based on the ideXlab platform.
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Structure-guided design of pyrazolo[1,5-a]pyrimidines as inhibitors of human Cyclin-Dependent Kinase 2.
Bioorganic & medicinal chemistry letters, 2005Co-Authors: Douglas S. Williamson, Martin J. Parratt, Justin Bower, Jonathan D. Moore, Christine M. Richardson, Pawel Dokurno, Andrew Cansfield, Geraint L. Francis, Richard Hebdon, Rob HowesAbstract:Abstract The protein structure guided design of a series of pyrazolo[1,5-a]pyrimidines with high potency for human Cyclin-Dependent Kinase 2 (CDK2) is described. Some examples were shown to inhibit the growth of human colon tumour cells, were equipotent for CDK1 and were selective against GSK-3β and other Kinases.
Tang Huai-hao - One of the best experts on this subject based on the ideXlab platform.
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Expression of Cyclin-Dependent Kinase 2 in non-small cell lung cancer and its clinical significance
Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2003Co-Authors: Tang Huai-haoAbstract:Objective To investigate the clinical significance of expression of Cyclin-Dependent Kinase 2(CDK2) in non-small cell lung cancer (NSCLC). Methods Specimens of formalin-fixed, paraffin embedded NSCLC ( n =66) and normal lung tissues ( n =12) were analyzed by streptavidin/peroxidase conjugate method of immunohistochemistry (S-P) for the expression of CDK2 and its relationship with clinical prognosis. Results In 66 NSCLC cases, the expression of CDK2 showed nuclear immunoreactivity. The positive expression rates of CDK2 was 84.85%. Some of the clinical parameters (age, sex, histology, stage, lymph node involvement) had no significant correlation with expression of CDK2,but pathologic grade and extent of tumour size had a significant correlation with expression of CDK2( P 0.05). The time of survival was significantly shorter in patients with CDK2 positive than those with CDK2 negative ( P =0.014). The estimated increased relative risk for patients with CDK2 positive tumours was 2.5 . Conclusion The expression of CDK2 shows nuclear immunoreactivity in NSCLC tissues, its over-expression is related to some of the clinical pathological parameters and the poor prognosis of NSCLC patients.
Wolfgang E. Berdel - One of the best experts on this subject based on the ideXlab platform.
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Cyclin E is the Only Cyclin-Dependent Kinase 2-associated Cyclin that Predicts Metastasis and Survival in Early Stage Non-Small Cell Lung Cancer
Cancer research, 2001Co-Authors: Carsten Müller-tidow, Ralf Metzger, Katrin Kügler, Sven Diederichs, Gregory Idos, Michael Thomas, Barbara Dockhorn-dworniczak, Paul M. Schneider, H. Phillip Koeffler, Wolfgang E. BerdelAbstract:Progression through G 1 -S transition and S phase of the cell cycle is mediated by Cyclin-Dependent Kinase 2 (cdk2), which interacts with several cyclins. Two of these, cyclin E and cyclin A2 (also known as cyclin A), are overexpressed in many cancers. Cyclin E2 and cyclin A1 are recently discovered cdk2-interacting cyclins that are found in malignant tumor cell lines and in acute myeloid leukemia, respectively. Expression and prognostic role of these cyclins in solid tumors is unknown. Here, we have analyzed expression and prognostic relevance of the cdk2-associated cyclins in non-small cell lung cancer (NSCLC). Fresh-frozen biopsies ( n = 70) from completely resected tumors with stage I to IIIA NSCLC were studied. Gene expression was analyzed by quantitative real-time reverse transcription-PCR. Expression levels of cyclin E ( P = 0.04) and cyclin A2 ( P = 0.004) were significantly higher in the tumor samples than in normal controls. Cyclin A1 , cyclin A2 , and cyclin E2 expression levels did not have prognostic relevance for survival. The mean survival time associated with low and high levels of cyclin E was 69.4 and 47.2 months, respectively, which was statistically significant ( P = 0.03). Differences in survival were particularly pronounced in stages I and II. Cyclin E was also closely associated with the development of distant metastasis ( P = 0.01). Finally, we confirmed by immunohistochemistry analyses that cyclin E mRNA expression was closely associated with cyclin E protein expression. In conclusion, cyclin E is a strong independent prognostic indicator in patients with early-stage NSCLC, whereas cyclin E2 , cyclin A1 , and cyclin A2 do not have a prognostic role in NSCLC.
Rodrigo Recabarren - One of the best experts on this subject based on the ideXlab platform.
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Mechanistic insights into the phosphoryl transfer reaction in Cyclin-Dependent Kinase 2: A QM/MM study.
PloS one, 2019Co-Authors: Rodrigo Recabarren, Edison Osorio, Julio Caballero, Iñaki Tuñón, Jans Alzate-moralesAbstract:Cyclin-Dependent Kinase 2 (CDK2) is an important member of the CDK family exerting its most important function in the regulation of the cell cycle. It catalyzes the transfer of the gamma phosphate group from an ATP (adenosine triphosphate) molecule to a Serine/Threonine residue of a peptide substrate. Due to the importance of this enzyme, and protein Kinases in general, a detailed understanding of the reaction mechanism is desired. Thus, in this work the phosphoryl transfer reaction catalyzed by CDK2 was revisited and studied by means of hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. Our results suggest that the base-assisted mechanism is preferred over the substrate-assisted pathway when one Mg2+ is present in the active site, in agreement with a previous theoretical study. The base-assisted mechanism resulted to be dissociative, with a potential energy barrier of 14.3 kcal/mol, very close to the experimental derived value. An interesting feature of the mechanism is the proton transfer from Lys129 to the phosphoryl group at the second transition state, event that could be helping in neutralizing the charge on the phosphoryl group upon the absence of a second Mg2+ ion. Furthermore, important insights into the mechanisms in terms of bond order and charge analysis were provided. These descriptors helped to characterize the synchronicity of bond forming and breaking events, and to characterize charge transfer effects. Local interactions at the active site are key to modulate the charge distribution on the phosphoryl group and therefore alter its reactivity.
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Mechanistic insights into the phosphoryl transfer reaction in Cyclin-Dependent Kinase 2: a QM/MM study
2019Co-Authors: Rodrigo Recabarren, Edison Osorio, Julio Caballero, Iñaki Tuñón, Jans Alzate-moralesAbstract:Abstract Cyclin-Dependent Kinase 2 (CDK2) is an important member of the CDK family exerting its most important function in the regulation of the cell cycle. It catalyzes the transfer of the gamma phosphate group from an ATP (adenosine triphosphate) molecule to a Serine/Threonine residue of a peptide substrate. Due to the importance of this enzyme, and protein Kinases in general, a detailed understanding of the reaction mechanism is desired. Thus, in this work the phosphoryl transfer reaction catalyzed by CDK2 was revisited and studied by means of hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. Our results show that the base-assisted mechanism is preferred over the substrate-assisted pathway, in agreement with a previous theoretical study. The base-assisted mechanism resulted to be dissociative, with a potential energy barrier of 14.3 kcal/mol, very close to the experimental derived value. An interesting feature of the mechanism is the proton transfer from Lys129 to the phosphoryl group at the second transition state, event that could be helping in neutralizing the charge on the phosphoryl group upon the absence of a second Mg2+ ion. Furthermore, important insights into the mechanisms in terms of bond order and charge analysis were provided. These descriptors helped to characterize the synchronicity of bond forming and breaking events, and to characterize charge transfer effects. Local interactions at the active site are key to modulate the charge distribution on the phosphoryl group and therefore alter its reactivity.
