scholarly journals APE1 distinguishes DNA substrates in exonucleolytic cleavage by induced space-filling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tung-Chang Liu ◽  
Chun-Ting Lin ◽  
Kai-Cheng Chang ◽  
Kai-Wei Guo ◽  
Shuying Wang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Nucleoside Analogs ◽  
Structural Features ◽  
Structural Basis ◽  
Complex Structures ◽  
Exonuclease Activity ◽  
Substrate Selection ◽  
Space Filling ◽  
Repair Pathways ◽  
First Time

AbstractThe exonuclease activity of Apurinic/apyrimidinic endonuclease 1 (APE1) is responsible for processing matched/mismatched terminus in various DNA repair pathways and for removing nucleoside analogs associated with drug resistance. To fill in the gap of structural basis for exonucleolytic cleavage, we determine the APE1-dsDNA complex structures displaying end-binding. As an exonuclease, APE1 does not show base preference but can distinguish dsDNAs with different structural features. Integration with assaying enzyme activity and binding affinity for a variety of substrates reveals for the first time that both endonucleolytic and exonucleolytic cleavage can be understood by an induced space-filling model. Binding dsDNA induces RM (Arg176 and Met269) bridge that defines a long and narrow product pocket for exquisite machinery of substrate selection. Our study paves the way to comprehend end-processing of dsDNA in the cell and the drug resistance relating to APE1.

scholarly journals Domain integration of ADAM family proteins: Emerging themes from structural studies

2019 ◽  
Vol 244 (17) ◽  
pp. 1510-1519
Author(s):  
Tom CM Seegar ◽  
Stephen C Blacklow
Keyword(s):  
Cell Adhesion ◽  
Historical Context ◽  
Structural Features ◽  
Cellular Adhesion ◽  
Structural Basis ◽  
Future Research ◽  
Ectodomain Shedding ◽  
Substrate Selection ◽  
New Findings ◽  
Domain Integration

ADAM (a disintegrin and metalloproteinase) proteins are type-1 transmembrane and secreted proteins that function in cell adhesion and signal transduction. Here we review the structural features of ADAM proteins that direct their biological functions in ectodomain shedding and cell adhesion. Impact statement Recent structural advances have provided a deeper appreciation for interdomain relationships that modulate the activity of ADAM proteins in ectodomain shedding and cellular adhesion. Our review covers these new findings, and places them into historical context. The new results make clear that the metalloproteinase domain works in combination with its ancillary domains to execute its biological function. The ADAM ectodomain is dynamic, and accesses conformations that require interdomain movements during its enzymatic “lifecycle.” Fundamental questions about ADAM activation and substrate selection, however, still remain unanswered. Elucidating the biochemical and structural basis for ADAM regulation will be an exciting avenue of future research that should greatly advance our understanding of ADAM function in biology and human pathogenesis.

scholarly journals UV Inscription and Pressure Induced Long-Period Gratings through 3D Printed Amplitude Masks

Sensors ◽  
2021 ◽  
Vol 21 (6) ◽  
pp. 1977
Author(s):  
Ricardo Oliveira ◽  
Liliana M. Sousa ◽  
Ana M. Rocha ◽  
Rogério Nogueira ◽  
Lúcia Bilro
Keyword(s):  
State Of The Art ◽  
Low Cost ◽  
Resonance Wavelength ◽  
Complex Structures ◽  
Pressing Method ◽  
Long Period ◽  
Long Period Gratings ◽  
3D Printed ◽  
Mechanical Pressing ◽  
First Time

In this work, we demonstrate for the first time the capability to inscribe long-period gratings (LPGs) with UV radiation using simple and low cost amplitude masks fabricated with a consumer grade 3D printer. The spectrum obtained for a grating with 690 µm period and 38 mm length presented good quality, showing sharp resonances (i.e., 3 dB bandwidth < 3 nm), low out-of-band loss (~0.2 dB), and dip losses up to 18 dB. Furthermore, the capability to select the resonance wavelength has been demonstrated using different amplitude mask periods. The customization of the masks makes it possible to fabricate gratings with complex structures. Additionally, the simplicity in 3D printing an amplitude mask solves the problem of the lack of amplitude masks on the market and avoids the use of high resolution motorized stages, as is the case of the point-by-point technique. Finally, the 3D printed masks were also used to induce LPGs using the mechanical pressing method. Due to the better resolution of these masks compared to ones described on the state of the art, we were able to induce gratings with higher quality, such as low out-of-band loss (0.6 dB), reduced spectral ripples, and narrow bandwidths (~3 nm).

scholarly journals Efficient overcoming of drug resistance to anticancer nucleoside analogs by nanodelivery of active phosphorylated drugs

2010 ◽  
Vol 395 (1-2) ◽  
pp. 281-289 ◽  
Author(s):  
Carlos M. Galmarini ◽  
Galya Warren ◽  
Madapathage T. Senanayake ◽  
Serguei V. Vinogradov
Keyword(s):  
Drug Resistance ◽  
Nucleoside Analogs

scholarly journals Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qin Gong ◽  
Kim Robinson ◽  
Chenrui Xu ◽  
Phuong Thao Huynh ◽  
Kelvin Han Chung Chong ◽  
...  
Keyword(s):  
Cell Death ◽  
Inner Core ◽  
Inflammatory Diseases ◽  
Structural Features ◽  
Structural Basis ◽  
Cultured Human Cells ◽  
Structural Insight ◽  
Sensor Proteins ◽  
Insight Into

AbstractNod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related sensor proteins NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, their mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIINDUPA. Biochemically, self-assembled NLRP1-CARD filaments are sufficient to drive ASC speck formation in cultured human cells—a process that is greatly enhanced by NLRP1-FIINDUPA which forms oligomers in vitro. The cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments, solved here at 3.7 Å, uncover unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide structural insight into the mechanisms of activation for human NLRP1 and CARD8 and reveal how highly specific signaling can be achieved by heterotypic CARD interactions within the inflammasome complexes.

scholarly journals An Application of Fit Quality to Screen MDM2/p53 Protein-Protein Interaction Inhibitors

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3174 ◽  
Author(s):  
Xin Xue ◽  
Gang Bao ◽  
Hai-Qing Zhang ◽  
Ning-Yi Zhao ◽  
Yuan Sun ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Drug Target ◽  
P53 Protein ◽  
Pharmacophore Model ◽  
Cellular Level ◽  
Complex Structures ◽  
Ligand Complex ◽  
Null Cell ◽  
Protein Protein Interaction ◽  
First Time

: The judicious application of ligand or binding efficiency (LE) metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Here we report for the first time the use of LE based metric, fit quality (FQ), in virtual screening (VS) of MDM2/p53 protein-protein interaction inhibitors (PPIIs). Firstly, a Receptor-Ligand pharmacophore model was constructed on multiple MDM2/ligand complex structures to screen the library. The enrichment factor (EF) for screening was calculated based on a decoy set to define the screening threshold. Finally, 1% of the library, 335 compounds, were screened and re-filtered with the FQ metric. According to the statistical results of FQ vs activity of 156 MDM2/p53 PPIIs extracted from literatures, the cut-off was defined as FQ = 0.8. After the second round of VS, six compounds with the FQ > 0.8 were picked out for assessing their antitumor activity. At the cellular level, the six hits exhibited a good selectivity (larger than 3) against HepG2 (wt-p53) vs Hep3B (p53 null) cell lines. On the further study, the six hits exhibited an acceptable affinity (range of Ki from 102 to 103 nM) to MDM2 when comparing to Nutlin-3a. Based on our work, FQ based VS strategy could be applied to discover other PPIIs.

Exploring the Contribution of Mycobacteria Characteristics in Their Interaction with Human Macrophages

2013 ◽  
Vol 19 (5) ◽  
pp. 1159-1169 ◽  
Author(s):  
Carla Silva ◽  
Joao Perdigao ◽  
Elsa Alverca ◽  
António P. Alves de Matos ◽  
Patricia A. Carvalho ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Envelope ◽  
Treatment Strategies ◽  
Human Monocyte ◽  
Selective Advantage ◽  
Multidrug Resistant ◽  
Structural Features ◽  
Major Health Problem ◽  
Transmission Electron ◽  
Mdr Tb

AbstractTuberculosis (TB) is a major health problem. The emergence of multidrug resistant (MDR)Mycobacterium tuberculosis(Mtb) isolates confounds treatment strategies. In Portugal, cases of MDR-TB are reported annually with an increased incidence noted in Lisbon. The majority of these MDR-TB cases are due to closely related mycobacteria known collectively as theLisboafamily and Q1 cluster. Genetic determinants linked to drug resistance have been exhaustively studied resulting in the identification of family and cluster specific mutations. Nevertheless, little is known about other factors involved in development of mycobacteria drug resistance. Here, we complement genetic analysis with the study of morphological and structural features of theLisboafamily and Q1 cluster isolates by using scanning and transmission electron microscopy. This analysis allowed the identification of structural differences, such as cell envelope thickness, between Mtb clinical isolates that are correlated with antibiotic resistance. The infection of human monocyte derived macrophages allowed us to document the relative selective advantage of theLisboafamily isolates over other circulating Mtb isolates.

How Crystals Form from a Cloud of Atoms

2011 ◽  
Vol 675-677 ◽  
pp. 3-7
Author(s):  
Peter Häussler ◽  
Martin Stiehler
Keyword(s):  
Structure Formation ◽  
Fundamental Equation ◽  
Structural Features ◽  
Local Order ◽  
Total System ◽  
Angular Momenta ◽  
General Dynamics ◽  
Bloch’S Theorem ◽  
The Given ◽  
First Time

Structure formation, the condensation of a cloud of atoms to a crystal is still not well understood. Disordered sytems (amorphous/liquid) should be in the center of this research, they are the precursors of any crystal. We consider elementary systems, as well as binary, or ternary amorphous alloys, irrespective whether they are metallically, covalently or ionically bonded and describe the process of structure formation in the formal language of thermodynamics but, as far as we know for the first time, by an extended version (general dynamics), based on the complete Gibbs fundamental equation, applied to internal subsystems. Major structural features evolve from global resonances between formerly independent internal subsystems by exchanging momenta and angular momenta, both accompanied by energy. By this they adjust mutually their internal features and create spherical-periodic structural order at medium-range distances. Under the given external constraints the resonances get optimized by selforganization. Global resonances of the type considered have clearly to be distinguished from local resonances between individual ions (described by quantum chemistry) forming local order. The global resonances cause anti-bonding (non-equilibrium) as well as bonding (equilibrium) states of the coupled total system, occupying the latter to form new structurally extended order. The transition to equilibrium creates entropy which itself leaves the system together with energy. At resonance the energetical splitting between the bonding and anti-bonding state is largest, the creation of entropy and the decrease of the total energy therefore, too. The crystal, finally, evolves by additionally optimizing a resonance based on angular momentum, and the additional adjustments of the local resonances to the global ones, theoretically done by applying Bloch’s theorem.

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