testosterone (ARG101) / arGentis - LARVOL DELTA

#TRAVERSE trial insights: A comprehensive look at testosterone replacement therapy and cardiovascular safety. @RKSayyid @UofT and @zklaassen_md @GACancerCenter join in this UroToday #JournalClub discussion > https://bit.ly/46RwSBr @NEJM @LincoffMichael

A two-component monooxygenase for continuous denitration and dechlorination of chlorinated 4-nitrophenol in Ensifer sp. strain 22-1. (PubMed, Environ Res) - "Homologous modeling and docking showed that Val155∼Ala159, Phe206∼Pro209 and Phe446∼Arg461 of CnpA participated in the formation of the FAD-binding pocket, and Arg101, Val155 and Asn447 formed hydrogen bonds with 2,6-DCNP/2C4NP in the substrate-binding pocket. This work characterized a new two-component monooxygenase for 2,6-DCNP and 2C4NP, and enriched our understanding of the degradation mechanism of chlorinated nitrophenols (CNPs) by microorganisms."

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Structural analysis of metal chelation of the metalloproteinase thermolysin by 1,10-phenanthroline. (PubMed, J Inorg Biochem) - "Moreover, interactions with Ser5 and Arg101 were also observed...Ca at the Ca3 site exposed to the solvent was chelated by 1,10-phenanthroline, resulting in a conformational change in the side chain of Asp56 and Gln61. Based on the surface structure, for 1,10-phenanthroline to chelate a metal, it is important that the metal is exposed on the protein surface and that there is no steric hindrance impairing 1,10-phenanthroline access by the amino acids around the metal."

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[VIRTUAL] Whole-Exome Sequencing Identifies Likely Causative Variants in Four Candidate Genes in 16 Families with Spina Bifida (KIDNEY WEEK 2020) - "In family B4197 with myelomeningocele, we identified a TBXT het missense mutation (c.301C>T; p. Arg101Cys)... Through whole exome sequencing, we detected likely deleterious mutations in 4 of 16 cases with a diagnosis of SB. We show that composing a list of 95 candidate genes based on established mouse models and genes known to be related to SB in human facilitates the detection of monogenic causes for SB. We are expanding this study to a larger cohort."

Rab35/ACAP2 and Rab35/RUSC2 Complex Structures Reveal Molecular Basis for Effector Recognition by Rab35 GTPase. (PubMed, Structure) - "In the Rab35/RUSC2 complex structure, Arg1015 of RUSC2 functions as a "pseudo-arginine finger" that stabilizes the GTP-bound Rab35, thus facilitating the assembly of Rab35/RUSC2 complex. The structural analysis allows us to design specific Rab35 mutants capable of eliminating Rab35/ACAP2 and Rab35/RUSC2 interactions, but not interfering with other effector bindings. The atomic structures also offer possible explanations to disease-associated mutants identified at the Rab35-effector interfaces."

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Two clusters of surface-exposed amino acid residues enable high-affinity binding of retinal degeneration-3 (RD3) protein to retinal guanylyl cyclase. (PubMed, J Biol Chem) - "The second cluster surrounded Arg-101 on a surface of helix 3...In contrast, deletion of 49 C-terminal residues did not affect the apparent affinity of RD3 for RetGC. Our findings identify the functional interface on RD3 required for its inhibitory binding to RetGC, a process essential for protecting photoreceptors from degeneration."

Journal • Ophthalmology

Arginine-95 is important for recruiting superoxide to the active site of the FerB flavoenzyme of Paracoccus denitrificans. (PubMed, FEBS Lett) - "The crystal structure of ChrR was previously determined with a chloride bound proximal to FMN in the vicinity of Arg101, and the authors suggested that the anionic electron acceptors, chromate and uranyl tricarbonate, bind similarly...Stopped-flow data for the flavin cofactor showed that the oxidative step is rate-limiting for catalytic turnover. The findings are consistent with a role for FerB as a superoxide scavenging contributor."

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A Single Cleavage Reaction in the Proteolytic Activation of Factor V to the Cofactor Is Rate-Limiting in a Step That Is Selectively Dependent on Anion Binding Exosite 2 of Thrombin (ASH 2017) - "Occlusion of ABE2 by the covalently linked propiece in mIIa variants greatly impairs their ability to activate hFV to the active cofactor by selectively decreasing the rate of cleavage at Arg1545. The surprising and near absolute need for cleavage at Arg1545 to produce cofactor is consistent with new biochemical and structural evidence implicating an essential role played by an acidic sequence immediately N-terminal to Arg1545 in concert with a basic sequence C-terminal to Arg1018 within the B domain in restricting the binding of Xa to the incompletely cleaved procofactor and preventing cofactor function."

Biosimilar • Hematological Malignancies • Venous Thromboembolism

Cloning, expression, and characterization of a novel heparinase I from Bacteroides eggerthii. (PubMed, Prep Biochem Biotechnol) - "Substrate docking study revealed that Lys99, Arg101, Gln241, Lys270, Asn275, and Lys292 were mainly involved in the substrate binding of Hep I. The shorter hydrogen bonds formed between heparin and these residues suggested the higher specific activity of BeHep I. And the minimum conformational entropy value of 756 J·K provides an evidence for the improved stability of this enzyme. This Hep I could be of interest in the industrial preparation of LMWH for its high specific activity and good stability."

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Novel STAG3 mutations in a Caucasian family with primary ovarian insufficiency. (PubMed, Mol Genet Genomics) - "We identified two novel pathogenic variants in STAG3 encoding a meiosis-specific subunit of the cohesin ring, which ensures correct sister chromatid cohesion: a c.3052delC truncating mutation in exon 28 yielding p.Arg1018Aspfs*14, and a c.659T > G substitution in exon seven yielding p.Leu220Arg...In conclusion, this observation shows the necessity to perform the genetic study of POI worldwide including STAG3. This could lead to appropriate genetic counseling and long term follow-up since these patients may develop ovarian tumors."

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