scholarly journals Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action

2021 ◽  
Vol 22 (6) ◽  
pp. 2806
Author(s):  
Paweł Łukasik ◽  
Irena Baranowska-Bosiacka ◽  
Katarzyna Kulczycka ◽  
Izabela Gutowska
Keyword(s):  
Small Molecule ◽  
Catalytic Domain ◽  
Three Dimensional ◽  
Binding Pocket ◽  
Point Of View ◽  
Dimensional Structure ◽  
Future Research ◽  
Atp Binding ◽  
Cdk Inhibitors ◽  
Wide Range

Recent studies on cyclin-dependent kinase (CDK) inhibitors have revealed that small molecule drugs have become very attractive for the treatment of cancer and neurodegenerative disorders. Most CDK inhibitors have been developed to target the ATP binding pocket. However, CDK kinases possess a very similar catalytic domain and three-dimensional structure. These features make it difficult to achieve required selectivity. Therefore, inhibitors which bind outside the ATP binding site present a great interest in the biomedical field, both from the fundamental point of view and for the wide range of their potential applications. This review tries to explain whether the ATP competitive inhibitors are still an option for future research, and highlights alternative approaches to discover more selective and potent small molecule inhibitors.

Applications of 3D printing in critical care medicine: A scoping review

2021 ◽  
pp. 0310057X2097665
Author(s):  
Natasha Abeysekera ◽  
Kirsty A Whitmore ◽  
Ashvini Abeysekera ◽  
George Pang ◽  
Kevin B Laupland
Keyword(s):  
Critical Care ◽  
Scoping Review ◽  
A Priori ◽  
Three Dimensional ◽  
Critical Care Medicine ◽  
Future Research ◽  
Care Practice ◽  
Three Dimensional Printing ◽  
Wide Range ◽  
Dimensional Printing

Although a wide range of medical applications for three-dimensional printing technology have been recognised, little has been described about its utility in critical care medicine. The aim of this review was to identify three-dimensional printing applications related to critical care practice. A scoping review of the literature was conducted via a systematic search of three databases. A priori specified themes included airway management, procedural support, and simulation and medical education. The search identified 1544 articles, of which 65 were included. Ranging across many applications, most were published since 2016 in non – critical care discipline-specific journals. Most studies related to the application of three-dimensional printed models of simulation and reported good fidelity; however, several studies reported that the models poorly represented human tissue characteristics. Randomised controlled trials found some models were equivalent to commercial airway-related skills trainers. Several studies relating to the use of three-dimensional printing model simulations for spinal and neuraxial procedures reported a high degree of realism, including ultrasonography applications three-dimensional printing technologies. This scoping review identified several novel applications for three-dimensional printing in critical care medicine. Three-dimensional printing technologies have been under-utilised in critical care and provide opportunities for future research.

The first crystal structure of the peptidase domain of the U32 peptidase family

2015 ◽  
Vol 71 (12) ◽  
pp. 2505-2512 ◽  
Author(s):  
Magdalena Schacherl ◽  
Angelika A. M. Montada ◽  
Elena Brunstein ◽  
Ulrich Baumann
Keyword(s):  
Crystal Structure ◽  
Catalytic Mechanism ◽  
Quaternary Structure ◽  
Catalytic Domain ◽  
Three Dimensional ◽  
Zinc Ion ◽  
Crystal Structure Analysis ◽  
Dimensional Structure ◽  
Sequence Motifs ◽  
Conserved Sequence

The U32 family is a collection of over 2500 annotated peptidases in the MEROPS database with unknown catalytic mechanism. They mainly occur in bacteria and archaea, but a few representatives have also been identified in eukarya. Many of the U32 members have been linked to pathogenicity, such as proteins fromHelicobacterandSalmonella. The first crystal structure analysis of a U32 catalytic domain fromMethanopyrus kandleri(genemk0906) reveals a modified (βα)8TIM-barrel fold with some unique features. The connecting segment between strands β7 and β8 is extended and helix α7 is located on top of the C-terminal end of the barrel body. The protein exhibits a dimeric quaternary structure in which a zinc ion is symmetrically bound by histidine and cysteine side chains from both monomers. These residues reside in conserved sequence motifs. No typical proteolytic motifs are discernible in the three-dimensional structure, and biochemical assays failed to demonstrate proteolytic activity. A tunnel in which an acetate ion is bound is located in the C-terminal part of the β-barrel. Two hydrophobic grooves lead to a tunnel at the C-terminal end of the barrel in which an acetate ion is bound. One of the grooves binds to aStrep-Tag II of another dimer in the crystal lattice. Thus, these grooves may be binding sites for hydrophobic peptides or other ligands.

scholarly journals Structure of the Lectin Mannose 6-Phosphate Receptor Homology (MRH) Domain of Glucosidase II, an Enzyme That Regulates Glycoprotein Folding Quality Control in the Endoplasmic Reticulum

2013 ◽  
Vol 288 (23) ◽  
pp. 16460-16475 ◽  
Author(s):  
Linda J. Olson ◽  
Ramiro Orsi ◽  
Solana G. Alculumbre ◽  
Francis C. Peterson ◽  
Ivan D. Stigliano ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Three Dimensional ◽  
Binding Pocket ◽  
Dimensional Structure ◽  
Mannose Residue ◽  
Glucosidase Ii ◽  
Mannose 6 Phosphate ◽  
First Time ◽  
Conserved Residue

Here we report for the first time the three-dimensional structure of a mannose 6-phosphate receptor homology (MRH) domain present in a protein with enzymatic activity, glucosidase II (GII). GII is involved in glycoprotein folding in the endoplasmic reticulum. GII removes the two innermost glucose residues from the Glc3Man9GlcNAc2 transferred to nascent proteins and the glucose added by UDP-Glc:glycoprotein glucosyltransferase. GII is composed of a catalytic GIIα subunit and a regulatory GIIβ subunit. GIIβ participates in the endoplasmic reticulum localization of GIIα and mediates in vivo enhancement of N-glycan trimming by GII through its C-terminal MRH domain. We determined the structure of a functional GIIβ MRH domain by NMR spectroscopy. It adopts a β-barrel fold similar to that of other MRH domains, but its binding pocket is the most shallow known to date as it accommodates a single mannose residue. In addition, we identified a conserved residue outside the binding pocket (Trp-409) present in GIIβ but not in other MRHs that influences GII glucose trimming activity.

scholarly journals Crystal structure of microtubule affinity-regulating kinase 4 catalytic domain in complex with a pyrazolopyrimidine inhibitor

2016 ◽  
Vol 72 (2) ◽  
pp. 129-134 ◽  
Author(s):  
John S. Sack ◽  
Mian Gao ◽  
Susan E. Kiefer ◽  
Joseph E. Myers ◽  
John A. Newitt ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Catalytic Domain ◽  
Neurofibrillary Tangle ◽  
Binding Pocket ◽  
Atp Binding ◽  
Activation Loop ◽  
Serine Threonine Kinase ◽  
Atp Binding Site ◽  
Threonine Kinase ◽  
Catalytic Loop

Microtubule-associated protein/microtubule affinity-regulating kinase 4 (MARK4) is a serine/threonine kinase involved in the phosphorylation of MAP proteins that regulate microtubule dynamics. Abnormal activity of MARK4 has been proposed to contribute to neurofibrillary tangle formation in Alzheimer's disease. The crystal structure of the catalytic and ubiquitin-associated domains of MARK4 with a potent pyrazolopyrimidine inhibitor has been determined to 2.8 Å resolution with anRworkof 22.8%. The overall structure of MARK4 is similar to those of the other known MARK isoforms. The inhibitor is located in the ATP-binding site, with the pyrazolopyrimidine group interacting with the inter-lobe hinge region while the aminocyclohexane moiety interacts with the catalytic loop and the DFG motif, forcing the activation loop out of the ATP-binding pocket.

scholarly journals Oscillatory and steady streaming flow in the anterior chamber of the moving eye

2019 ◽  
Vol 863 ◽  
pp. 904-926 ◽  
Author(s):  
M. Dvoriashyna ◽  
R. Repetto ◽  
J. H. Tweedy
Keyword(s):  
Anterior Chamber ◽  
Fluid Motion ◽  
Three Dimensional ◽  
Frequency Component ◽  
Dominant Frequency ◽  
Point Of View ◽  
Dimensional Structure ◽  
Steady Streaming ◽  
Constant Height ◽  
Angular Amplitude

We study the flow induced by eye rotations in the anterior chamber (AC) of the eye, the region between the cornea and the iris. We model the geometry of the AC as a thin domain sitting on the surface of a sphere, and study both the simpler case of a constant-height domain as well as a more realistic AC shape. We model eye rotations as harmonic in time with prescribed frequency $\unicode[STIX]{x1D714}_{f}$ and amplitude $\unicode[STIX]{x1D6FD}$, and use lubrication theory to simplify the governing equations. We write the equations in a reference frame moving with the domain and show that fluid motion is governed by three dimensionless parameters: the aspect ratio $\unicode[STIX]{x1D716}$ of the AC, the angular amplitude $\unicode[STIX]{x1D6FD}$ and the Womersley number $\unicode[STIX]{x1D6FC}$. We simplify the equations under the physiologically realistic assumptions that $\unicode[STIX]{x1D716}$ is small and $\unicode[STIX]{x1D6FC}$ large, leading to a linear system that can be decomposed into three harmonics: a dominant frequency component, with frequency $\unicode[STIX]{x1D714}_{f}$, and a steady streaming component and a third component with frequency $2\unicode[STIX]{x1D714}_{f}$. We solve the problem analytically for the constant-height domain and numerically as the solution of ordinary differential equations in the more realistic geometry. Both the primary flow and the steady streaming are shown to have a highly three-dimensional structure, which has not been highlighted in previous numerical works. We show that the steady streaming is particularly relevant from the clinical point of view, as it induces fluid mixing in the AC. Furthermore, the steady flow component is the dominant mixing mechanism during the night, when the thermal flow induced by temperature variations across the AC is suppressed.

Hemoglobin Biosynthesis in Vitreoscilla stercoraria DW: Cloning, Expression, and Characterization of a New Homolog of a Bacterial Globin Gene

1998 ◽  
Vol 64 (6) ◽  
pp. 2220-2228 ◽  
Author(s):  
Meenal Joshi ◽  
Shekhar Mande ◽  
Kanak L. Dikshit
Keyword(s):  
Globin Gene ◽  
Three Dimensional ◽  
Fold Increase ◽  
Binding Pocket ◽  
Growth Conditions ◽  
Dimensional Structure ◽  
Strictly Aerobic ◽  
Coding Region ◽  
Oxygen Control ◽  
Constitutive Production

ABSTRACT In the strictly aerobic, gram-negative bacteriumVitreoscilla strain C1, oxygen-limited growth conditions create a more than 50-fold increase in the expression of a homodimeric heme protein which was recognized as the first bacterial hemoglobin (Hb). The recently determined crystal structure ofVitreoscilla Hb has indicated that the heme pocket of microbial globins differs from that of eukaryotic Hbs. In an attempt to understand the diverse functions of Hb-like proteins in prokaryotes, we have cloned and characterized the gene (vgb) encoding an Hb-like protein from another strain of Vitreoscilla,V. stercoraria DW. Several silent changes were observed within the coding region of the V. stercoraria vgb gene. Apart from that, V. stercoraria Hb exhibited interesting differences between the A and E helices. Compared to its Hb counterpart from Vitreoscilla strain C1, the purified preparation ofV. stercoraria Hb displays a slower autooxidation rate. The differences between Vitreoscilla Hb and V. stercoraria Hb were mapped onto the three-dimensional structure of Vitreoscilla Hb, which indicated that the four changes, namely, Ile7Val, Ile9Thr, Ile10Ser, and Leu62Val, present within theV. stercoraria Hb fall in the region where the A and E helices contact each other. Therefore, alteration in the relative orientation of the A and E helices and the corresponding conformational change in the heme binding pocket of V. stercoraria Hb can be correlated to its slower autooxidation rate. In sharp contrast to the oxygen-regulated biosynthesis of Hb in Vitreoscillastrain C1, production of Hb in V. stercoraria has been found to be low and independent of oxygen control, which is supported by the absence of a fumarate and nitrate reductase regulator box within the V. stercoraria vgb promoter region. Thus, the regulation mechanisms of the Hb-encoding gene appear to be quite different in the two closely related species ofVitreoscilla. The relatively slower autooxidation rate ofV. stercoraria Hb, lack of oxygen sensitivity, and constitutive production of Hb suggest that it may have some other function(s) in the cellular physiology of V. stercorariaDW, together with facilitated oxygen transport, predicted for earlier reported Vitreoscilla Hb.

Structural modeling and role of HAX-1 as a positive allosteric modulator of human serine protease HtrA2

2019 ◽  
Vol 476 (20) ◽  
pp. 2965-2980
Author(s):  
Lalith K. Chaganti ◽  
Shubhankar Dutta ◽  
Raja Reddy Kuppili ◽  
Mriganka Mandal ◽  
Kakoli Bose
Keyword(s):  
Pdz Domain ◽  
Limited Proteolysis ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Multifunctional Protein ◽  
Promising Therapeutic Target ◽  
Wide Range ◽  
Structural Details ◽  
Structural Architecture ◽  
First Time

Abstract HAX-1, a multifunctional protein involved in cell proliferation, calcium homeostasis, and regulation of apoptosis, is a promising therapeutic target. It regulates apoptosis through multiple pathways, understanding of which is limited by the obscurity of its structural details and its intricate interaction with its cellular partners. Therefore, using computational modeling, biochemical, functional enzymology and spectroscopic tools, we predicted the structure of HAX-1 as well as delineated its interaction with one of it pro-apoptotic partner, HtrA2. In this study, three-dimensional structure of HAX-1 was predicted by threading and ab initio tools that were validated using limited proteolysis and fluorescence quenching studies. Our pull-down studies distinctly demonstrate that the interaction of HtrA2 with HAX-1 is directly through its protease domain and not via the conventional PDZ domain. Enzymology studies further depicted that HAX-1 acts as an allosteric activator of HtrA2. This ‘allosteric regulation’ offers promising opportunities for the specific control and functional modulation of a wide range of biological processes associated with HtrA2. Hence, this study for the first time dissects the structural architecture of HAX-1 and elucidates its role in PDZ-independent activation of HtrA2.

scholarly journals Recent development of SPR spectroscopy as potential method for diagnosis of dengue virus E-protein

Sensor Review ◽  
2018 ◽  
Vol 38 (1) ◽  
pp. 106-116 ◽  
Author(s):  
Nur Alia Sheh Omar ◽  
Yap Wing Fen
Keyword(s):  
Thin Films ◽  
Dengue Virus ◽  
Three Dimensional ◽  
Optical Biosensor ◽  
Future Research ◽  
Multilayer Thin Films ◽  
Content Type ◽  
Sensing Applications ◽  
E Protein ◽  
Wide Range

Purpose This paper aims to review the potential application of surface plasmon resonance (SPR) in diagnosis of dengue virus (DENV-2) E-protein and the development of SPR to become an alternative DENV sensor. Design/methodology/approach In this review, the existing standard laboratory techniques to diagnosis of DENV are discussed, together with their drawbacks. To overcome these drawbacks, SPR has been aimed to be a valuable optical biosensor for identification of antibodies to the DENV antigen. The review also includes the future studies on three-dimensional poly(amidoamine) (PAMAM) dendrimer-surface-assembled monolayer (SAM)-Au multilayer thin films, which are envisaged to have high potential sensitive and selective detection ability toward target E-proteins. Findings Application of SPR in diagnosis of DENV emerged over recent years. A wide range of immobilized biorecognition molecules have been developed to combine with SPR as an effective sensor. The detection limit, sensitivity and selectivity of SPR sensing in DENV have been enhanced from time to time, until the present. Originality/value The main purpose of this review is to provide authors with up-to-date and useful information on sensing DENV using SPR and to introduce a novel three-dimensional PAMAM-SAM-Au multilayer thin films for future research on SPR sensing applications.

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