Cyclin-Dependent Kinase 2 in Cellular Senescence and Cancer. A Structural and Functional Review

2019 ◽  
Vol 20 (7) ◽  
pp. 716-726 ◽  
Author(s):  
Priscylla Andrade Volkart ◽  
Gabriela Bitencourt-Ferreira ◽  
André Arigony Souto ◽  
Walter Filgueira de Azevedo
Keyword(s):  
Binding Affinity ◽  
Cellular Senescence ◽  
Cell Cycle Progression ◽  
Structural Information ◽  
Structural Basis ◽  
Cyclin Dependent Kinase ◽  
New Era ◽  
Functional Studies ◽  
Molecular Aspects

<P>Background: Cyclin-dependent kinase 2 (CDK2) has been studied due to its role in the cell-cycle progression. The elucidation of the CDK2 structure paved the way to investigate the molecular basis for inhibition of this enzyme, with the coordinated efforts combining crystallography with functional studies. </P><P> Objective: Our goal here is to review recent functional and structural studies directed to understanding the role of CDK2 in cancer and senescence. </P><P> Methods: There are over four hundreds of crystallographic structures available for CDK2, many of them with binding affinity information. We use this abundance of data to analyze the essential features responsible for the inhibition of CDK2 and its function in cancer and senescence. </P><P> Results: The structural and affinity data available CDK2 makes it possible to have a clear view of the vital CDK2 residues involved in molecular recognition. A detailed description of the structural basis for ligand binding is of pivotal importance in the design of CDK2 inhibitors. Our analysis shows the relevance of the residues Leu 83 and Asp 86 for binding affinity. The recent findings revealing the participation of CDK2 inhibition in senescence open the possibility to explore the richness of structural and affinity data for a new era in the development of CDK2 inhibitors, targeting cellular senescence. </P><P> Conclusion: Here, we analyzed structural information for CDK2 in combination with inhibitors and mapped the molecular aspects behind the strongest CDK2 inhibitors for which structures and ligandbinding affinity data were available. From this analysis, we identified the significant intermolecular interactions responsible for binding affinity. This knowledge may guide the future development of CDK2 inhibitors targeting cancer and cellular senescence.</P>

scholarly journals Structural Basis of Chemokine Receptor Function—A Model for Binding Affinity and Ligand Selectivity

2006 ◽  
Vol 26 (5) ◽  
pp. 325-339 ◽  
Author(s):  
Lavanya Rajagopalan ◽  
Krishna Rajarathnam
Keyword(s):  
Binding Affinity ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Structural Information ◽  
Structural Basis ◽  
Ligand Selectivity ◽  
Site Model ◽  
Terminal Loop ◽  
Chemokine Ligands ◽  
G Protein Coupled

Chemokine receptors play fundamental roles in human physiology from embryogenesis to inflammatory response. The receptors belong to the G-protein coupled receptor class, and are activated by chemokine ligands with a range of specificities and affinities that result in a complicated network of interactions. The molecular basis for function is largely a black box, and can be directly attributed to the lack of structural information on the receptors. Studies to date indicate that function can be best described by a two-site model, that involves interactions between the receptor N-domain and ligand N-terminal loop residues (site-I), and between receptor extracellular loop and the ligand N-terminal residues (site-II). In this review, we describe how the two-site model could modulate binding affinity and ligand selectivity, and also highlight some of the unique chemokine receptor features, and their role in function.

scholarly journals Crystal Structures of Two Coronavirus ADP-Ribose-1″-Monophosphatases and Their Complexes with ADP-Ribose: a Systematic Structural Analysis of the Viral ADRP Domain

2008 ◽  
Vol 83 (2) ◽  
pp. 1083-1092 ◽  
Author(s):  
Yuanyuan Xu ◽  
Le Cong ◽  
Cheng Chen ◽  
Lei Wei ◽  
Qi Zhao ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Crystal Structures ◽  
Structural Information ◽  
Large Family ◽  
Binding Pocket ◽  
Structural Basis ◽  
Active Site Residues ◽  
Replication Process ◽  
Functional Studies ◽  
Group I

ABSTRACT The coronaviruses are a large family of plus-strand RNA viruses that cause a wide variety of diseases both in humans and in other organisms. The coronaviruses are composed of three main lineages and have a complex organization of nonstructural proteins (nsp's). In the coronavirus, nsp3 resides a domain with the macroH2A-like fold and ADP-ribose-1"-monophosphatase (ADRP) activity, which is proposed to play a regulatory role in the replication process. However, the significance of this domain for the coronaviruses is still poorly understood due to the lack of structural information from different lineages. We have determined the crystal structures of two viral ADRP domains, from the group I human coronavirus 229E and the group III avian infectious bronchitis virus, as well as their respective complexes with ADP-ribose. The structures were individually solved to elucidate the structural similarities and differences of the ADRP domains among various coronavirus species. The active-site residues responsible for mediating ADRP activity were found to be highly conserved in terms of both sequence alignment and structural superposition, whereas the substrate binding pocket exhibited variations in structure but not in sequence. Together with data from a previous analysis of the ADRP domain from the group II severe acute respiratory syndrome coronavirus and from other related functional studies of ADRP domains, a systematic structural analysis of the coronavirus ADRP domains was realized for the first time to provide a structural basis for the function of this domain in the coronavirus replication process.

scholarly journals The Multiple Roles of the Cdc14 Phosphatase in Cell Cycle Control

2020 ◽  
Vol 21 (3) ◽  
pp. 709
Author(s):  
Javier Manzano-López ◽  
Fernando Monje-Casas
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Current Knowledge ◽  
Cell Cycle Control ◽  
Multiple Roles ◽  
Special Focus ◽  
Cyclin Dependent Kinase ◽  
Yeast Saccharomyces Cerevisiae ◽  
Cycle Progression

The Cdc14 phosphatase is a key regulator of mitosis in the budding yeast Saccharomyces cerevisiae. Cdc14 was initially described as playing an essential role in the control of cell cycle progression by promoting mitotic exit on the basis of its capacity to counteract the activity of the cyclin-dependent kinase Cdc28/Cdk1. A compiling body of evidence, however, has later demonstrated that this phosphatase plays other multiple roles in the regulation of mitosis at different cell cycle stages. Here, we summarize our current knowledge about the pivotal role of Cdc14 in cell cycle control, with a special focus in the most recently uncovered functions of the phosphatase.

scholarly journals Structural basis for the role of serine-rich repeat proteins from Lactobacillus reuteri in gut microbe–host interactions

2018 ◽  
Vol 115 (12) ◽  
pp. E2706-E2715 ◽  
Author(s):  
Saannya Sequeira ◽  
Devon Kavanaugh ◽  
Donald A. MacKenzie ◽  
Tanja Šuligoj ◽  
Samuel Walpole ◽  
...  
Keyword(s):  
Lactobacillus Reuteri ◽  
Structural Information ◽  
Bacterial Species ◽  
Surface Proteins ◽  
Structural Basis ◽  
Gene Encoding ◽  
Rhamnogalacturonan I ◽  
Host Microbe Interactions ◽  
Dynamics Simulations

Lactobacillus reuteri, a Gram-positive bacterial species inhabiting the gastrointestinal tract of vertebrates, displays remarkable host adaptation. Previous mutational analyses of rodent strain L. reuteri 100-23C identified a gene encoding a predicted surface-exposed serine-rich repeat protein (SRRP100-23) that was vital for L. reuteri biofilm formation in mice. SRRPs have emerged as an important group of surface proteins on many pathogens, but no structural information is available in commensal bacteria. Here we report the 2.00-Å and 1.92-Å crystal structures of the binding regions (BRs) of SRRP100-23 and SRRP53608 from L. reuteri ATCC 53608, revealing a unique β-solenoid fold in this important adhesin family. SRRP53608-BR bound to host epithelial cells and DNA at neutral pH and recognized polygalacturonic acid (PGA), rhamnogalacturonan I, or chondroitin sulfate A at acidic pH. Mutagenesis confirmed the role of the BR putative binding site in the interaction of SRRP53608-BR with PGA. Long molecular dynamics simulations showed that SRRP53608-BR undergoes a pH-dependent conformational change. Together, these findings provide mechanistic insights into the role of SRRPs in host–microbe interactions and open avenues of research into the use of biofilm-forming probiotics against clinically important pathogens.

scholarly journals The Role of the Cyclin Dependent Kinase Inhibitor p21cip1/waf1 in Targeting Cancer: Molecular Mechanisms and Novel Therapeutics

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1475 ◽  
Author(s):  
Al Bitar ◽  
Gali-Muhtasib
Keyword(s):  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Biological Activities ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Multiple Signaling ◽  
Made In

p21cip1/waf1 mediates various biological activities by sensing and responding to multiple stimuli, via p53-dependent and independent pathways. p21 is known to act as a tumor suppressor mainly by inhibiting cell cycle progression and allowing DNA repair. Significant advances have been made in elucidating the potential role of p21 in promoting tumorigenesis. Here, we discuss the involvement of p21 in multiple signaling pathways, its dual role in cancer, and the importance of understanding its paradoxical functions for effectively designing therapeutic strategies that could selectively inhibit its oncogenic activities, override resistance to therapy and yet preserve its tumor suppressive functions.

scholarly journals The Role of miRNAs as Therapeutic Tools in Sickle Cell Disease

Medicina ◽  
2021 ◽  
Vol 57 (10) ◽  
pp. 1106
Author(s):  
Cyril Cyrus
Keyword(s):  
Sickle Cell ◽  
Cell Cycle Progression ◽  
Globin Gene ◽  
Erythroid Differentiation ◽  
Clinical Severity ◽  
Functional Studies ◽  
Abnormal Hemoglobin ◽  
Therapeutic Tools ◽  
Targeted Medicine

Background and Objectives: Sickle cell disorder (SCD) is a paradigmatic example of a complex monogenic disorder. SCD is characterized by the production of abnormal hemoglobin, primarily in the deoxygenated state, which makes erythrocytes susceptible to intracellular hemoglobin polymerization. Functional studies have affirmed that the dysregulation of miRNAs enhances clinical severity or has an ameliorating effect in SCD. miRNAs can be effectively regulated to reduce the pace of cell cycle progression, to reduce iron levels, to influence hemolysis and oxidative stress, and most importantly, to increase γ-globin gene expression and enhance the effectiveness of hydroxyurea. Results: This review highlights the roles played by some key miRNAs in hemoglobinopathies, especially in hematopoiesis, erythroid differentiation, and severity of anemia, which make miRNAs attractive molecular tools for innovative therapeutic approaches. Conclusion: In this era of targeted medicine, miRNAs mimics and antagomirs may be promising inducers of HbF synthesis which could ameliorate the clinical severity of SCD.

scholarly journals Molecular basis for the interaction between Integrator subunits IntS9 and IntS11 and its functional importance

2017 ◽  
Vol 114 (17) ◽  
pp. 4394-4399 ◽  
Author(s):  
Yixuan Wu ◽  
Todd R. Albrecht ◽  
David Baillat ◽  
Eric J. Wagner ◽  
Liang Tong
Keyword(s):  
Rna Polymerase Ii ◽  
Structural Information ◽  
Stable Complex ◽  
Small Nuclear Rna ◽  
Functional Studies ◽  
Enhancer Rna ◽  
Molecular Mechanism Of Action ◽  
Β Sheet ◽  
Two Hybrid

The metazoan Integrator complex (INT) has important functions in the 3′-end processing of noncoding RNAs, including the uridine-rich small nuclear RNA (UsnRNA) and enhancer RNA (eRNA), and in the transcription of coding genes by RNA polymerase II. The INT contains at least 14 subunits, but its molecular mechanism of action is poorly understood, because currently there is little structural information about its subunits. The endonuclease activity of INT is mediated by its subunit 11 (IntS11), which belongs to the metallo-β-lactamase superfamily and is a paralog of CPSF-73, the endonuclease for pre-mRNA 3′-end processing. IntS11 forms a stable complex with Integrator complex subunit 9 (IntS9) through their C-terminal domains (CTDs). Here, we report the crystal structure of the IntS9–IntS11 CTD complex at 2.1-Å resolution and detailed, structure-based biochemical and functional studies. The complex is composed of a continuous nine-stranded β-sheet with four strands from IntS9 and five from IntS11. Highly conserved residues are located in the extensive interface between the two CTDs. Yeast two-hybrid assays and coimmunoprecipitation experiments confirm the structural observations on the complex. Functional studies demonstrate that the IntS9–IntS11 interaction is crucial for the role of INT in snRNA 3′-end processing.

scholarly journals Structure Activity Relationship of Xanthones for Inhibition of Cyclin Dependent Kinase 4 from Mangosteen (Garcinia Mangostana L.

2019 ◽  
Vol 4 (4) ◽  
pp. 38-45 ◽  
Author(s):  
Bhaskar Vemu ◽  
Mirielle C. Nauman ◽  
Jacob P. Veenstra ◽  
Jeremy J. Johnson
Keyword(s):  
Cell Cycle Progression ◽  
Cyclin Dependent Kinase ◽  
Garcinia Mangostana ◽  
Cycle Progression ◽  
Structure Activity ◽  
A Cell ◽  
Key Functional Groups ◽  
Relationship Of ◽  
Unique Chemical

The mangosteen fruit is a popular Southeast Asian fruit consumed for centuries. There have been a variety of xanthones isolated from the fruit, bark, roots and leaves with each having unique chemical and physical properties. Previously, the most abundant xanthone α-mangostin has been shown to inhibit CDK4. Herein we describe the role of selected xanthones from the mangosteen inhibiting CDK4. The evidence we provide here is that key functional groups are required to inhibit the CDK4 protein to prevent the phosphorylation of downstream targets critical to inhibiting uncontrolled cell cycle progression. To define the properties of xanthones for inhibiting CDK4 we utilized a cell free biochemical assay to identify inhibitors of CDK4. The following xanthones were used for the analysis: α-mangostin, β-mangostin, γ-mangostin, gartanin, 8-desoxygartanin, garcinone C and garcinone D, 9-hydroxycalabaxanthone, and 3-isomangostin These results further substantiate the unique pharmacological properties of individual xanthones and how a mixture of xanthones may be responsible for a multi-targeted effect in cell based pharmacology systems.

scholarly journals Structural basis of the heterodimerization of the MST and RASSF SARAH domains in the Hippo signalling pathway

2014 ◽  
Vol 70 (7) ◽  
pp. 1944-1953 ◽  
Author(s):  
Eunha Hwang ◽  
Hae-Kap Cheong ◽  
Ameeq Ul Mushtaq ◽  
Hye-Yeon Kim ◽  
Kwon Joo Yeo ◽  
...  
Keyword(s):  
Structural Information ◽  
Critical Role ◽  
Three Dimensional ◽  
Helical Structure ◽  
Structural Features ◽  
Signalling Pathway ◽  
Structural Basis ◽  
X Ray Crystallography ◽  
Hippo Signalling

Despite recent progress in research on the Hippo signalling pathway, the structural information available in this area is extremely limited. Intriguingly, the homodimeric and heterodimeric interactions of mammalian sterile 20-like (MST) kinases through the so-called `SARAH' (SAV/RASSF/HPO) domains play a critical role in cellular homeostasis, dictating the fate of the cell regarding cell proliferation or apoptosis. To understand the mechanism of the heterodimerization of SARAH domains, the three-dimensional structures of an MST1–RASSF5 SARAH heterodimer and an MST2 SARAH homodimer were determined by X-ray crystallography and were analysed together with that previously determined for the MST1 SARAH homodimer. While the structure of the MST2 homodimer resembled that of the MST1 homodimer, the MST1–RASSF5 heterodimer showed distinct structural features. Firstly, the six N-terminal residues (Asp432–Lys437), which correspond to the short N-terminal 310-helix h1 kinked from the h2 helix in the MST1 homodimer, were disordered. Furthermore, the MST1 SARAH domain in the MST1–RASSF5 complex showed a longer helical structure (Ser438–Lys480) than that in the MST1 homodimer (Val441–Lys480). Moreover, extensive polar and nonpolar contacts in the MST1–RASSF5 SARAH domain were identified which strengthen the interactions in the heterodimer in comparison to the interactions in the homodimer. Denaturation experiments performed using urea also indicated that the MST–RASSF heterodimers are substantially more stable than the MST homodimers. These findings provide structural insights into the role of the MST1–RASSF5 SARAH domain in apoptosis signalling.

scholarly journals The AMPK/p27Kip1 Pathway as a Novel Target to Promote Autophagy and Resilience in Aged Cells

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1430
Author(s):  
Lauren K. McKay ◽  
James P. White
Keyword(s):  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Metabolic Stress ◽  
Subcellular Location ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cytoskeletal Dynamics ◽  
Novel Target

Once believed to solely function as a cyclin-dependent kinase inhibitor, p27Kip1 is now emerging as a critical mediator of autophagy, cytoskeletal dynamics, cell migration and apoptosis. During periods of metabolic stress, the subcellular location of p27Kip1 largely dictates its function. Cytoplasmic p27Kip1 has been found to be promote cellular resilience through autophagy and anti-apoptotic mechanisms. Nuclear p27Kip1, however, inhibits cell cycle progression and makes the cell susceptible to quiescence, apoptosis, and/or senescence. Cellular location of p27Kip1 is regulated, in part, by phosphorylation by various kinases, including Akt and AMPK. Aging promotes nuclear localization of p27Kip1 and a predisposition to senescence or apoptosis. Here, we will review the role of p27Kip1 in healthy and aging cells with a particular emphasis on the interplay between autophagy and apoptosis.

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