Published: Jan. 1, 2024
Language: Английский
Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)
Published: Feb. 16, 2025
Language: Английский
Citations
3
Protein Science, Journal Year: 2025, Volume and Issue: 34(2)
Published: Jan. 22, 2025
Abstract Neurofibromin (NF1), a Ras GTPase‐activating protein (GAP), catalyzes Ras‐mediated GTP hydrolysis and thereby negatively regulates the Ras/MAPK pathway. NF1 mutations can cause neurofibromatosis type 1 manifesting tumors, neurodevelopmental disorders. Exactly how missense in GAP‐related domain of (NF1 GRD ) allosterically impact GAP to promote these distinct pathologies is unclear. Especially tantalizing question same‐domain, same‐residue variants exhibit clinical phenotypes. Guided by data, we take up this dilemma. We sampled conformational ensembles complex with GTP‐bound K‐Ras4B performing molecular dynamics simulations. Our results show that retain active conformation but biased propensities catalytically competent populations K‐Ras4B–NF1 complex. In agreement depiction experimental tagging, compared wild type, E1356A E1356V mutants effectively act through loss‐of‐function gain‐of‐function mechanisms, leading developmental disorders, respectively. Allosteric modulation activity biasing different states further demonstrated diminished isoform 2, as powerful predictors function. Taken together, our work identifies hotspot could tune function, suggests targeting oncogenic restoring catalytic activity, offers mechanism for phenotypes determined their propensities.
Language: Английский
Citations
2
Science Advances, Journal Year: 2024, Volume and Issue: 10(27)
Published: July 5, 2024
Decades ago, mitogen-promoted signaling duration and strength were observed to be sensed by the cell critical for its decisions: proliferate or differentiate. Landmark publications established importance of mitogen not only in G 1 cycle phase but also through S 2 /M transition. Despite these early milestones, how signal strength, short strong weaker sustained, control fate has been largely unheeded. Here, we center on cardinal signaling-related questions, including (i) fluctuating mitogenic signals are converted into proliferation-differentiation decisions (ii) why extended weak is associated with differentiation, while bursts induce proliferation but, if too long, irreversible senescence. Our innovative broad outlook harnesses biology protein conformational ensembles, helping us define clarify decisions, thus fate.
Language: Английский
Citations
14
Published: Jan. 1, 2025
Language: Английский
Citations
0
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown
Published: March 4, 2025
Abstract Cyclin-dependent kinases 4 and 6 (CDK4 CDK6) are key regulators of the G1-S phase transition in cell cycle. In cancer cells, CDK6 overexpression often outcompetes CDK4 driving cycle progression, contributing to resistance against CDK4/6 inhibitors (CDK4/6i). This suggests distinct functional conformational differences between these two kinases, despite their striking structural sequence similarities. Understanding mechanisms that differentiate is crucial, as CDK4/6i—frequently linked overexpression—remains a significant therapeutic challenge. Notably, upregulated CDK4/6i-resistant cancers rapidly proliferating hematopoietic stem underscoring its unique regulatory roles. We hypothesize dynamics explain phosphorylation retinoblastoma protein, Rb, inhibitor efficacy, control. leads us question how dissimilar encode actions . To elucidate differential activities, molecular mechanisms, binding, we combine biochemical assays (MD) simulations. discover have allosteric networks connecting β3-αC loop G-loop. exhibits stronger coupling shorter path lengths regions, resulting higher kinase activity upon cyclin binding impacting specificity. also an unrecognized role unstructured C-terminus, which allosterically connects stabilizes R-spine, facilitating slightly activity. Our findings bridge gap similarity divergence CDK6, advancing understanding regulation biology. Graphical abstract
Language: Английский
Citations
0
International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 142303 - 142303
Published: March 1, 2025
Language: Английский
Citations
0
Cells, Journal Year: 2024, Volume and Issue: 13(19), P. 1656 - 1656
Published: Oct. 6, 2024
Protein kinases have essential responsibilities in controlling several cellular processes, and their abnormal regulation is strongly related to the development of cancer. The implementation protein kinase inhibitors has significantly transformed cancer therapy by modifying treatment strategies. These received substantial FDA clearance recent decades. emerged as primary objectives for therapeutic interventions, particularly context treatment. At present, 69 therapeutics been approved that target approximately 24 kinases, which are specifically prescribed neoplastic illnesses. novel agents inhibit certain such receptor protein-tyrosine protein-serine/threonine dual-specificity nonreceptor kinases. This review presents a comprehensive overview targets inhibitors, with specific focus on cyclin-dependent (CDKs) epidermal growth factor (EGFR). majority reviewed studies commenced an assessment cell lines concluded biological evaluation individual targets. articles provide detailed information structural features potent anticancer activity, refers ability selectively cancer-promoting including CDKs EGFR. Additionally, latest FDA-approved targeting these enzymes were highlighted accordingly.
Language: Английский
Citations
3
The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: unknown
Published: Sept. 24, 2024
Cyclin-dependent kinases (CDKs) are activated upon cyclin-binding to enable progression through the cell cycle. Dominant CDKs and cyclins in mammalian cells include CDK1, CDK2, CDK4, CDK6 corresponding A, B, D, E. While only certain, "typical" cyclin/CDK complexes primarily responsible for cycle progression, "atypical" can form sometimes perform same roles as typical complexes. We asked what structural features of favor formation complexes, a vital yet not fully explored question. use computational docking biophysical analyses exhaustively evaluate structure stability all CDK cyclin listed above. find that binding is generally stronger than atypical especially when an active conformation. Typical have denser clusters, indicating they more defined sites Our results help explain three notable function cycle: (i) why CDK4 cyclin-D exceptionally high specificity each other; (ii) both cyclin-A cyclin-B strongly activate whereas CDK2 by cyclin-A; (iii) cyclin-E normally activates but CDK1. Overall, this work reveals modalities how lead preference versus differ between observations suggest targeting catalytic actions destabilizing their native differential interfaces.
Language: Английский
Citations
2
Molecules, Journal Year: 2024, Volume and Issue: 29(22), P. 5334 - 5334
Published: Nov. 13, 2024
Neoplastic cells are characterized by uncontrolled cell divisions caused cycle dysregulation. Key regulatory proteins governing the transition from G1 to S phase CDK4 and CDK6 kinases, which controlled D-type cyclins. The CDK4/6 kinases enable use of these as targets for anticancer therapy because they prevent growth development malignant inhibiting their activity. This paper surveys clinical trial results concerning palbociclib, first in-class FDA-approved drug hormone-dependent breast cancer. It discusses therapeutic applications in cancer well solid tumors hematopoietic malignancies. Additionally, presents an analysis palbociclib resistance acquired during explores new approaches, such modifications that enhance its desired activity or open up possibilities (PROTACs).
Language: Английский
Citations
0
Published: Jan. 1, 2024
Language: Английский
Citations
0