148 research outputs found
Structural basis of SALM3 dimerization and synaptic adhesion complex formation with PTPΟ
bioRxiv: doi: https://doi.org/10.1101/2020.01.09.893701Synaptic adhesion molecules play an important role in the formation, maintenance and refinement of neuronal connectivity. Recently, several leucine rich repeat (LRR) domain containing neuronal adhesion molecules have been characterized including netrin G-ligands, SLITRKs and the synaptic adhesion-like molecules (SALMs). Dysregulation of these adhesion molecules have been genetically and functionally linked to various neurological disorders. Here we investigated the molecular structure and mechanism of ligand interactions for the postsynaptic SALM3 adhesion protein with its presynaptic ligand, receptor protein tyrosine phosphatase sigma (PTP sigma). We solved the crystal structure of the dimerized LRR domain of SALM3, revealing the conserved structural features and mechanism of dimerization. Furthermore, we determined the complex structure of SALM3 with PTP sigma using small angle X-ray scattering, revealing a 2:2 complex similar to that observed for SALM5. Solution studies unraveled additional flexibility for the complex structure, but validated the uniform mode of action for SALM3 and SALM5 to promote synapse formation. The relevance of the key interface residues was further confirmed by mutational analysis with cellular binding assays and artificial synapse formation assays. Collectively, our results suggest that SALM3 dimerization is a pre-requisite for the SALM3-PTP sigma complex to exert synaptogenic activity.Peer reviewe
Effects of low frequency ultrasound on some properties of fibrinogen and its plasminolysis
<p>Abstract</p> <p>Background</p> <p>Pharmacological thrombolysis with streptokinase, urokinase or tissue activator of plasminogen (t-PA), and mechanical interventions are frequently used in the treatment of both arterial and venous thrombotic diseases. It has been previously reported that application of ultrasound as an adjunct to thrombolytic therapy offers unique potential to improve effectiveness. However, little is known about effects of the ultrasound on proteins of blood coagulation and fibrinolysis. Here, we investigated the effects of the ultrasound on fibrinogen on processes of coagulation and fibrinogenolysis in an <it>in vitro </it>system.</p> <p>Results</p> <p>Our study demonstrated that low frequency high intensity pulse ultrasound (25.1 kHz, 48.4 W/cm2, duty 50%) induced denaturation of plasminogen and t-PA and fibrinogen aggregates formation <it>in vitro</it>. The aggregates were characterized by the loss of clotting ability and a greater rate of plasminolysis than native fibrinogen. We investigated the effect of the ultrasound on individual proteins. In case of plasminogen and t-PA, ultrasound led to a decrease of the fibrinogenolysis rate, while it increased the fibrinogenolysis rate in case of fibrinogen. It has been shown that upon ultrasound treatment of mixture fibrinogen or fibrin with plasminogen, t-PA, or both, the rate of proteolytic digestion of fibrin(ogen) increases too. It has been shown that summary effect on the fibrin(ogen) proteolytic degradation under the conditions for combined ultrasound treatment is determined exclusively by effect on fibrin(ogen).</p> <p>Conclusions</p> <p>The data presented here suggest that among proteins of fibrinolytic systems, the fibrinogen is one of the most sensitive proteins to the action of ultrasound. It has been shown <it>in vitro </it>that ultrasound induced fibrinogen aggregates formation, characterized by the loss of clotting ability and a greater rate of plasminolysis than native fibrinogen in different model systems and under different mode of ultrasound treatment. Under ultrasound treatment of plasminogen and/or t-PA in the presence of fibrin(ogen) the stabilizing effect fibrin(ogen) on given proteins was shown. On the other hand, an increase in the rate of fibrin(ogen) lysis was observed due to both the change in the substrate structure and promoting of the protein-protein complexes formation.</p
Tardigrade workbench: comparing stress-related proteins, sequence-similar and functional protein clusters as well as RNA elements in tardigrades
<p>Abstract</p> <p>Background</p> <p>Tardigrades represent an animal phylum with extraordinary resistance to environmental stress.</p> <p>Results</p> <p>To gain insights into their stress-specific adaptation potential, major clusters of related and similar proteins are identified, as well as specific functional clusters delineated comparing all tardigrades and individual species (<it>Milnesium tardigradum</it>, <it>Hypsibius dujardini</it>, <it>Echiniscus testudo</it>, <it>Tulinus stephaniae</it>, <it>Richtersius coronifer</it>) and functional elements in tardigrade mRNAs are analysed. We find that 39.3% of the total sequences clustered in 58 clusters of more than 20 proteins. Among these are ten tardigrade specific as well as a number of stress-specific protein clusters. Tardigrade-specific functional adaptations include strong protein, DNA- and redox protection, maintenance and protein recycling. Specific regulatory elements regulate tardigrade mRNA stability such as lox P DICE elements whereas 14 other RNA elements of higher eukaryotes are not found. Further features of tardigrade specific adaption are rapidly identified by sequence and/or pattern search on the web-tool tardigrade analyzer <url>http://waterbear.bioapps.biozentrum.uni-wuerzburg.de</url>. The work-bench offers nucleotide pattern analysis for promotor and regulatory element detection (tardigrade specific; nrdb) as well as rapid COG search for function assignments including species-specific repositories of all analysed data.</p> <p>Conclusion</p> <p>Different protein clusters and regulatory elements implicated in tardigrade stress adaptations are analysed including unpublished tardigrade sequences.</p
Transcriptome Analysis in Tardigrade Species Reveals Specific Molecular Pathways for Stress Adaptations
Tardigrades have unique stress-adaptations that allow them to survive extremes of cold, heat, radiation and vacuum. To study this, encoded protein clusters and pathways from an ongoing transcriptome study on the tardigrade Milnesium tardigradum were analyzed using bioinformatics tools and compared to expressed sequence tags (ESTs) from Hypsibius dujardini, revealing major pathways involved in resistance against extreme environmental conditions. ESTs are available on the Tardigrade Workbench along with software and databank updates. Our analysis reveals that RNA stability motifs for M. tardigradum are different from typical motifs known from higher animals. M. tardigradum and H. dujardini protein clusters and conserved domains imply metabolic storage pathways for glycogen, glycolipids and specific secondary metabolism as well as stress response pathways (including heat shock proteins, bmh2, and specific repair pathways). Redox-, DNA-, stress- and protein protection pathways complement specific repair capabilities to achieve the strong robustness of M. tardigradum. These pathways are partly conserved in other animals and their manipulation could boost stress adaptation even in human cells. However, the unique combination of resistance and repair pathways make tardigrades and M. tardigradum in particular so highly stress resistant
ΠΠΈΠΏΠΎΡΠΈΠ»ΡΠ½ΠΎΡΡΡ BODIPY ΡΠ»ΡΠΎΡΠΎΡΠΎΡΠΎΠ² ΠΈ ΠΈΡ ΡΠ°ΡΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΠ΅ Π² ΡΠΈΡΡΠ΅ΠΌΠ΅ ΠΎΠΊΡΠ°Π½ΠΎΠ»-1βΠ²ΠΎΠ΄Π°
The work covers synthesis and lipophilicity estimation of several BODIPY dyes. For these compounds, the distribution between 1-octanol and water layers is experimentally described and the corresponding partition coefficients LogP are calculated. The experimental LogP values are compared with popular fragment-based methods XLopP3, ALogPS, WLogP, SILICOS-IT and MLogP. Additionally, the hydrophobic and polar surface areas are found with quantum-mechanical calculations. That allowed to find a correlation between the LogP coefficient and the molecular surface topology, as well as to determine the corresponding incremental values of the methyl, acetyl, and phenyl substituents.Β ΠΡΠΏΠΎΠ»Π½Π΅Π½ ΡΠΈΠ½ΡΠ΅Π· Π½Π΅ΡΠΊΠΎΠ»ΡΠΊΠΈΡ
BODIPY ΡΠ»ΡΠΎΡΠΎΡΠΎΡΠΎΠ² ΠΈ ΡΠ°ΡΡΠΌΠΎΡΡΠ΅Π½ΠΎ ΠΈΡ
ΡΠ°ΡΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΠ΅ Π² ΡΠΈΡΡΠ΅ΠΌΠ΅ ΠΎΠΊΡΠ°Π½ΠΎΠ»-1βΠ²ΠΎΠ΄Π°. ΠΠ»Ρ ΠΎΡΠ΅Π½ΠΊΠΈ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½ΠΈΡ ΡΠ°ΡΡΠ΅ΡΠ½ΡΡ
ΠΌΠ΅ΡΠΎΠ΄ΠΎΠ² ΠΏΡΠΈ ΠΎΠΏΠΈΡΠ°Π½ΠΈΠΈ Π»ΠΈΠΏΠΎΡΠΈΠ»ΡΠ½ΠΎΡΡΠΈ BODIPY ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΡΡ
ΠΎΠ±ΡΡΠΆΠ΄Π΅Π½Ρ ΡΠ°ΠΊΠΈΠ΅ ΠΏΠΎΠ΄Ρ
ΠΎΠ΄Ρ, ΠΊΠ°ΠΊ XLopP3, ALogPS, WLogP, SILICOS-IT ΠΈ MLogP. Π‘ ΠΏΠΎΠΌΠΎΡΡΡ ΠΊΠ²Π°Π½ΡΠΎΠ²ΠΎ-ΠΌΠ΅Ρ
Π°Π½ΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΠ°ΡΡΠ΅ΡΠΎΠ² Π½Π°ΠΉΠ΄Π΅Π½Ρ Π³ΠΈΠ΄ΡΠΎΡΠΎΠ±Π½Π°Ρ ΠΈ ΠΏΠΎΠ»ΡΡΠ½Π°Ρ ΠΏΠ»ΠΎΡΠ°Π΄ΠΈ ΠΌΠΎΠ»Π΅ΠΊΡΠ»ΡΡΠ½ΡΡ
ΠΏΠΎΠ²Π΅ΡΡ
Π½ΠΎΡΡΠ΅ΠΉ ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠΉ. ΠΡΠΎ ΠΏΠΎΠ·Π²ΠΎΠ»ΠΈΠ»ΠΎ ΡΡΡΠ°Π½ΠΎΠ²ΠΈΡΡ ΠΊΠΎΡΡΠ΅Π»ΡΡΠΈΡ ΠΌΠ΅ΠΆΠ΄Ρ ΠΊΠΎΡΡΡΠΈΡΠΈΠ΅Π½ΡΠΎΠΌ LogP ΠΈ ΡΠΎΠΏΠΎΠ»ΠΎΠ³ΠΈΠ΅ΠΉ ΠΌΠΎΠ»Π΅ΠΊΡΠ»ΡΡΠ½ΠΎΠΉ ΠΏΠΎΠ²Π΅ΡΡ
Π½ΠΎΡΡΠΈ, Π° ΡΠ°ΠΊΠΆΠ΅ ΠΎΠΏΡΠ΅Π΄Π΅Π»ΠΈΡΡ ΡΠΎΠΎΡΠ²Π΅ΡΡΡΠ²ΡΡΡΠΈΠ΅ Π²Π΅Π»ΠΈΡΠΈΠ½Ρ ΠΈΠ½ΠΊΡΠ΅ΠΌΠ΅Π½ΡΠΎΠ² Π΄Π»Ρ ΠΌΠ΅ΡΠΈΠ»ΡΠ½ΠΎΠ³ΠΎ, Π°ΡΠ΅ΡΠΈΠ»ΡΠ½ΠΎΠ³ΠΎ ΠΈ ΡΠ΅Π½ΠΈΠ»ΡΠ½ΠΎΠ³ΠΎ Π·Π°ΠΌΠ΅ΡΡΠΈΡΠ΅Π»Π΅ΠΉ
ΠΠΈΠΊΠ΅ΡΠΎΠ½Ρ ΠΏΡΠΈΡΠΎΠ΄Π½ΠΎΠ³ΠΎ ΠΏΡΠΎΠΈΡΡ ΠΎΠΆΠ΄Π΅Π½ΠΈΡ ΠΊΠ°ΠΊ ΠΏΠΎΡΠ΅Π½ΡΠΈΠ°Π»ΡΠ½ΡΠ΅ ΠΊΠΎΠ²Π°Π»Π΅Π½ΡΠ½ΡΠ΅ Π»ΠΈΠ³Π°Π½Π΄Ρ Π±Π΅Π»ΠΊΠΎΠ² SARS-CoV-2: ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠ΅ in silico ΠΌΠ΅ΡΠΎΠ΄ΠΎΠΌ Π΄ΠΎΠΊΠΈΠ½Π³Π°
Our computer-aided protein-ligand docking test using Autodock Vina software allowed to reveal the potential of few Ξ±- and Ξ²-diketones from plants and alternative living organisms as covalent ligands for few proteins of coronavirus SARS-CoV-2 β a causative agent of COVID-19. It has been established that values for energy of binding (docking score, Ebind, kcal/mol) less than β7.5 and for distances of ligandsβ carbonyl groups to side chain nitrogens of arginine residues of some coronaviral enzymes within 0.4 nm have been true for Ξ²-diketones 6-gingerdione (Pubchem code CID162952), 8-gingerdione (CID14440537), tetrahydrocurcumine (CID124072) as well as Ξ±-diketone wallitaxane E (CID132967478). The in silico revealed interactions are interesting to be verified in vitro and they point out a possibility of investigation of the compounds and related natural materials as tools for struggle against coronaviral infections.ΠΠΎΠΌΠΏΡΡΡΠ΅ΡΠ½ΡΠΉ Π΄ΠΎΠΊΠΈΠ½Π³, ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½Π½ΡΠΉ Ρ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½ΠΈΠ΅ΠΌ ΠΏΡΠΎΠ³ΡΠ°ΠΌΠΌΡ Autodock Vina, ΠΏΠΎΠ·Π²ΠΎΠ»ΠΈΠ» Π²ΡΡΠ²ΠΈΡΡ ΠΏΠΎΡΠ΅Π½ΡΠΈΠ°Π» Π½Π΅ΡΠΊΠΎΠ»ΡΠΊΠΈΡ
Ξ±- ΠΈ Ξ²-Π΄ΠΈΠΊΠ΅ΡΠΎΠ½ΠΎΠ² ΡΠ°ΡΡΠ΅Π½ΠΈΠΉ ΠΈ Π΄ΡΡΠ³ΠΈΡ
ΠΏΡΠΈΡΠΎΠ΄Π½ΡΡ
ΠΎΠ±ΡΠ΅ΠΊΡΠΎΠ² Π² ΠΊΠ°ΡΠ΅ΡΡΠ²Π΅ ΠΊΠΎΠ²Π°Π»Π΅Π½ΡΠ½ΡΡ
Π»ΠΈΠ³Π°Π½Π΄ΠΎΠ² ΡΡΠ΄Π° Π±Π΅Π»ΠΊΠΎΠ² ΠΊΠΎΡΠΎΠ½Π°Π²ΠΈΡΡΡΠ° SARS-CoV-2 β Π²ΠΎΠ·Π±ΡΠ΄ΠΈΡΠ΅Π»Ρ COVID-19. ΠΡΡΠ²Π»Π΅Π½ΠΎ, ΡΡΠΎ ΡΠ½Π΅ΡΠ³ΠΈΠ΅ΠΉ ΡΠ²ΡΠ·ΡΠ²Π°Π½ΠΈΡ (docking score, Ebind, ΠΊΠΊΠ°Π»/ΠΌΠΎΠ») ΠΌΠ΅Π½Π΅Π΅ β7,5 Ρ ΠΊΠΎΠ»ΠΎΠΊΠΎΠ»ΠΈΠ·Π°ΡΠΈΠ΅ΠΉ ΠΊΠ°ΡΠ±ΠΎΠ½ΠΈΠ»ΡΠ½ΡΡ
Π³ΡΡΠΏΠΏ Π½Π° ΡΠ°ΡΡΡΠΎΡΠ½ΠΈΠΈ Π½Π΅ Π±ΠΎΠ»Π΅Π΅ 0,4 Π½ΠΌ ΠΎΡ Π°ΡΠΎΠΌΠΎΠ² Π°Π·ΠΎΡΠ° Π±ΠΎΠΊΠΎΠ²ΠΎΠΉ ΡΠ΅ΠΏΠΈ ΠΎΡΡΠ°ΡΠΊΠΎΠ² Π°ΡΠ³ΠΈΠ½ΠΈΠ½Π° Π±Π΅Π»ΠΊΠΎΠ² ΠΊΠΎΡΠΎΠ½Π°Π²ΠΈΡΡΡΠ°. Ξ²-ΠΠΈΠΊΠ΅ΡΠΎΠ½Ρ 6-Π³ΠΈΠ½Π³Π΅ΡΠ΄ΠΈΠΎΠ½ (ΠΊΠΎΠ΄ ΡΡΡΡΠΊΡΡΡΡ ΠΏΠΎ Π±Π°Π·Π΅ Π΄Π°Π½Π½ΡΡ
Pubchem CID162952), 8-Π³ΠΈΠ½Π³Π΅ΡΠ΄ΠΈΠΎΠ½ (CID14440537), ΡΠ΅ΡΡΠ°Π³ΠΈΠ΄ΡΠΎΠΊΡΡΠΊΡΠΌΠΈΠ½ (CID124072), Π° ΡΠ°ΠΊΠΆΠ΅ Ξ±-Π΄ΠΈΠΊΠ΅ΡΠΎΠ½ Π²Π°Π»Π»ΠΈΡΠ°ΠΊΡΠ°Π½ E (CID132967478) ΠΎΠ±Π»Π°Π΄Π°Π»ΠΈ ΡΠ°ΠΊΠΈΠΌΠΈ ΡΠ²ΠΎΠΉΡΡΠ²Π°ΠΌΠΈ. ΠΡΡΠ²Π»Π΅Π½Π½ΡΠ΅ in silico Π²Π·Π°ΠΈΠΌΠΎΠ΄Π΅ΠΉΡΡΠ²ΠΈΡ ΡΠΊΠ°Π·ΡΠ²Π°ΡΡ Π½Π° Π²ΠΎΠ·ΠΌΠΎΠΆΠ½ΠΎΡΡΡ ΠΎΠ±Π½Π°ΡΡΠΆΠ΅Π½ΠΈΡ ΠΈΡ
Π² ΡΠΊΡΠΏΠ΅ΡΠΈΠΌΠ΅Π½ΡΠ΅ ΠΈ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ ΡΡΠΈΡ
Π²Π΅ΡΠ΅ΡΡΠ² ΠΈΠ»ΠΈ ΡΠΎΠ΄Π΅ΡΠΆΠ°ΡΠΈΡ
ΠΈΡ
ΠΏΡΠΈΡΠΎΠ΄Π½ΡΡ
ΠΌΠ°ΡΠ΅ΡΠΈΠ°Π»ΠΎΠ² ΠΊΠ°ΠΊ ΡΡΠ΅Π΄ΡΡΠ² Π±ΠΎΡΡΠ±Ρ Ρ ΠΊΠΎΡΠΎΠ½ΠΎΠ²ΠΈΡΡΡΠ½ΠΎΠΉ ΠΈΠ½ΡΠ΅ΠΊΡΠΈΠ΅ΠΉ
Multiβscale ensemble properties of the Escherichia coli RNA degradosome
Abstract: In organisms from all domains of life, multiβenzyme assemblies play central roles in defining transcript lifetimes and facilitating RNAβmediated regulation of gene expression. An assembly dedicated to such roles, known as the RNA degradosome, is found amongst bacteria from highly diverse lineages. About a fifth of the assembly mass of the degradosome of Escherichia coli and related species is predicted to be intrinsically disordered β a property that has been sustained for over a billion years of bacterial molecular history and stands in marked contrast to the high degree of sequence variation of that same region. Here, we characterize the conformational dynamics of the degradosome using a hybrid structural biology approach that combines solution scattering with ad hoc ensemble modelling, cryoβelectron microscopy, and other biophysical methods. The E. coli degradosome can form punctate bodies in vivo that may facilitate its functional activities, and based on our results, we propose an electrostatic switch model to account for the propensity of the degradosome to undergo programmable puncta formation
Π‘ΠΈΠ½ΡΠ΅Π· Π½ΠΎΠ²ΡΡ ΡΠΈΠ°Π·ΠΎΠ»ΠΎ[3,2-Π°]ΠΏΠΈΡΠΈΠΌΠΈΠ΄ΠΈΠ½ΠΎΠ² ΠΈ in silico Π°Π½Π°Π»ΠΈΠ· ΠΈΡ Π±ΠΈΠΎΠ°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ
An effective method of synthesis thiazolo[3,2-a]pyrimidine derivatives was developed and the compounds with n-pentyl or Ξ²-acetoxycyclopropyl as well as fluorescent benzo[f]coumarin substituents were obtained with yields 60 % and more. Using computational (in silico) approaches we demonstrated the ability of the obtained compounds to permeate lipid bilayer as well as their affinity to some protein kinases (compounds 4 and 6 bind with a protein kinase AKT1 with PDB code 3ΠΎ96; Autodock Vina-computed energy of binding (Ebind) values were -10.9 and -10.6 kcal/mol, respectively), acethylcholine esterase and some human cytochromes P450 (for P450 3A4, pdb 5vcd, Ebind -12.3 kcal/mol).Π Π°Π·ΡΠ°Π±ΠΎΡΠ°Π½ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΡΠΉ ΠΌΠ΅ΡΠΎΠ΄ ΠΏΠΎΠ»ΡΡΠ΅Π½ΠΈΡ ΠΈ ΡΠΈΠ½ΡΠ΅Π·ΠΈΡΠΎΠ²Π°Π½Ρ Π½ΠΎΠ²ΡΠ΅ ΡΠΈΠ°Π·ΠΎΠ»ΠΎ[3,2-a]ΠΏΠΈΡΠΈΠΌΠΈΠ΄ΠΈΠ½Ρ, ΡΠΎΠ΄Π΅ΡΠΆΠ°ΡΠΈΠ΅ Π½-ΠΏΠ΅Π½ΡΠ°Π½ΠΎΠ²ΡΠΉ ΠΈΠ»ΠΈ Ξ²-Π³ΠΈΠ΄ΡΠΎΠΊΡΠΈΡΠΈΠΊΠ»ΠΎΠΏΡΠΎΠΏΠ°Π½ΠΎΠ²ΡΠΉ, Π° ΡΠ°ΠΊΠΆΠ΅ ΡΠ»ΡΠΎΡΠ΅ΡΡΠΈΡΡΡΡΠΈΠΉ Π±Π΅Π½Π·ΠΎ[f]ΠΊΡΠΌΠ°ΡΠΈΠ½ΠΎΠ²ΡΠΉ Π·Π°ΠΌΠ΅ΡΡΠΈΡΠ΅Π»ΠΈ Ρ Π²ΡΡ
ΠΎΠ΄Π°ΠΌΠΈ Π±ΠΎΠ»Π΅Π΅ 60 %. ΠΠΎΠΌΠΏΡΡΡΠ΅ΡΠ½ΡΠΌΠΈ ΠΌΠ΅ΡΠΎΠ΄Π°ΠΌΠΈ (in silico) ΠΏΠΎΠΊΠ°Π·Π°Π½Π° ΡΠΏΠΎΡΠΎΠ±Π½ΠΎΡΡΡ ΠΏΠΎΠ»ΡΡΠ΅Π½Π½ΡΡ
ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠΉ ΠΏΡΠΎΠ½ΠΈΠΊΠ°ΡΡ ΡΠ΅ΡΠ΅Π· Π»ΠΈΠΏΠΈΠ΄Π½ΡΠΉ Π±ΠΈΡΠ»ΠΎΠΉ ΠΈ ΠΎΡΠ΅Π½Π΅Π½ΠΎ ΠΈΡ
ΡΡΠΎΠ΄ΡΡΠ²ΠΎ ΠΊ ΡΡΠ΄Ρ ΠΏΡΠΎΡΠ΅ΠΈΠ½ΠΊΠΈΠ½Π°Π· (ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΡ 4 ΠΈ 6 ΡΠ²ΡΠ·ΡΠ²Π°ΡΡΡΡ Ρ ΠΏΡΠΎΡΠ΅ΠΈΠ½ΠΊΠΈΠ½Π°Π·ΠΎΠΉ AKT1 Ρ ΠΊΠΎΠ΄ΠΎΠΌ PDB 3ΠΎ96; Π²Π΅Π»ΠΈΡΠΈΠ½Ρ, ΡΠ°ΡΡΡΠΈΡΡΠ²Π°Π΅ΠΌΡΠ΅ ΠΏΡΠΎΠ³ΡΠ°ΠΌΠΌΠΎΠΉ Autodock Vina ΡΠ½Π΅ΡΠ³ΠΈΠΈ ΡΠ²ΡΠ·ΡΠ²Π°Π½ΠΈΡ (Ebind), ΡΠΎΡΡΠ°Π²ΠΈΠ»ΠΈ: -10,9 ΠΈ -10,6 ΠΊΠΊΠ°Π»/ΠΌΠΎΠ»Ρ), Π°ΡΠ΅ΡΠΈΠ»Ρ
ΠΎΠ»ΠΈΠ½ΡΡΡΠ΅ΡΠ°Π·Π΅ ΠΈ ΡΠΈΡΠΎΡ
ΡΠΎΠΌΠ°ΠΌ P450 ΡΠ΅Π»ΠΎΠ²Π΅ΠΊΠ° (Π΄Π»Ρ ΡΠΈΡΠΎΡ
ΡΠΎΠΌΠ° P450 3A4, pdb 5vcd, Ebind -12,3 ΠΊΠΊΠ°Π»/ΠΌΠΎΠ»Ρ)
In silico ΠΎΡΠ΅Π½ΠΊΠ° Π½ΠΎΠ²ΡΡ Π°ΡΡΠΈΠ½Π½ΡΡ Π²Π·Π°ΠΈΠΌΠΎΠ΄Π΅ΠΉΡΡΠ²ΠΈΠΉ ΠΌΠ΅ΡΠΈΠ»ΠΊΡΠΌΠ°ΡΠΈΠ½Π° Ρ ΡΠΈΡΠΎΡ ΡΠΎΠΌΠ°ΠΌΠΈ P450
4-methyl-7-methoxycoumarin (CumOMe) has been synthesized and in silico calculations demonstrated localization of methoxy group within 0.4 nm from Fe ion of hem groups for some structures of human CYP19 & CYP46 as well as CYP152 S. paucimobilis, CYP158 St. coelicolor, HMUO C. diphtheriae, XPLA R. rhodochrous, CYP199A4 Rh. palustris, CYP101A1 Ps. putida and CYP51 M. tuberculosis.Π‘ΠΈΠ½ΡΠ΅Π·ΠΈΡΠΎΠ²Π°Π½ 4-ΠΌΠ΅ΡΠΈΠ»-7-ΠΌΠ΅ΡΠΎΠΊΡΠΈΠΊΡΠΌΠ°ΡΠΈΠ½ (CumOMe) ΠΈ in silico ΠΏΠΎΠΊΠ°Π·Π°Π½ΠΎ, ΡΡΠΎ Π»ΠΎΠΊΠ°Π»ΠΈΠ·Π°ΡΠΈΡ ΠΌΠ΅ΡΠΎΠΊΡΠΈΠ»ΡΠ½ΠΎΠ³ΠΎ ΡΡΠ°Π³ΠΌΠ΅Π½Π°ΡΠ° Π½Π° ΡΠ°ΡΡΡΠΎΡΠ½ΠΈΠΈ Π½Π΅ Π±ΠΎΠ»Π΅Π΅ 0,4 Π½ΠΌ ΠΎΡ ΠΆΠ΅Π»Π΅Π·Π° Π³Π΅ΠΌΠ° Π²ΠΎΠ·ΠΌΠΎΠΆΠ½Ρ Π΄Π»Ρ ΠΎΡΠ΄Π΅Π»ΡΠ½ΡΡ
ΡΡΡΡΠΊΡΡΡ CYP19A1 ΠΈ CYP46 ΡΠ΅Π»ΠΎΠ²Π΅ΠΊΠ°, Π° ΡΠ°ΠΊΠΆΠ΅ CYP152 S. paucimobilis, CYP158 St. coelicolor, HMUO C. diphtheriae, XPLA R. rhodochrous, CYP199A4 Rh. palustris, CYP101A1 Ps. Putida ΠΈ CYP51 M. tuberculosis
Analysis of the natively unstructured RNA/protein-recognition core in the Escherichia coli RNA degradosome and its interactions with regulatory RNA/Hfq complexes.
The RNA degradosome is a multi-enzyme assembly that plays a central role in the RNA metabolism of Escherichia coli and numerous other bacterial species including pathogens. At the core of the assembly is the endoribonuclease RNase E, one of the largest E. coli proteins and also one that bears the greatest region predicted to be natively unstructured. This extensive unstructured region, situated in the C-terminal half of RNase E, is punctuated with conserved short linear motifs that recruit partner proteins, direct RNA interactions, and enable association with the cytoplasmic membrane. We have structurally characterized a subassembly of the degradosome-comprising a 248-residue segment of the natively unstructured part of RNase E, the DEAD-box helicase RhlB and the glycolytic enzyme enolase, and provide evidence that it serves as a flexible recognition centre that can co-recruit small regulatory RNA and the RNA chaperone Hfq. Our results support a model in which the degradosome captures substrates and regulatory RNAs through the recognition centre, facilitates pairing to cognate transcripts and presents the target to the ribonuclease active sites of the greater assembly for cooperative degradation or processing
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