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1.
ACS Chem Neurosci ; 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-39012782

RESUMEN

Rexinoids are compounds that bind to the rexinoid X receptor (RXR) to modulate gene expression and have been proposed as a new class of therapeutics to treat Alzheimer's disease. Different rexinoids will initiate downstream effects that can be quite marked even though such compounds can be structurally similar and have comparable RXR binding affinities. RXR can both homo- and heterodimerize, and these protein-protein interactions and subsequent transactivating potential lead to differential gene expression, depending on the RXR dimeric partner, additional cofactors recruited, and downstream transcription factors that are up- or downregulated. Expression analysis was performed in the U87 human glioblastoma cell line treated with a panel of rexinoids, and our analysis demonstrated that rexinoids with similar RXR EC50 values can have pronounced differences in differential gene expression. Rexinoid binding likely leads to distinctive RXR conformations that cause major downstream gene expression alterations via modulation of RXR interacting proteins. Yeast two-hybrid analysis of RXR bait with two RXR interacting partners demonstrates that rexinoids drive differential binding of RXR to distinctive protein partners. Physiochemical analysis of the rexinoids reveals that the molecules cluster similarly to their gene expression patterns. Thus, rexinoids with similar RXR binding affinities drive differential gene expression by stimulating additional binding patterns in RXR and its homo- and heteropartners, driven by the physicochemical characteristics of these molecules.

2.
Acta Crystallogr F Struct Biol Commun ; 80(Pt 2): 43-51, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38305785

RESUMEN

The methylerythritol phosphate (MEP) pathway is a metabolic pathway that produces the isoprenoids isopentyl pyrophosphate and dimethylallyl pyrophosphate. Notably, the MEP pathway is present in bacteria and not in mammals, which makes the enzymes of the MEP pathway attractive targets for discovering new anti-infective agents due to the reduced chances of off-target interactions leading to side effects. There are seven enzymes in the MEP pathway, the third of which is IspD. Two crystal structures of Burkholderia thailandensis IspD (BtIspD) were determined: an apo structure and that of a complex with cytidine triphosphate (CTP). Comparison of the CTP-bound BtIspD structure with the apo structure revealed that CTP binding stabilizes the loop composed of residues 13-19. The apo structure of Mycobacterium paratuberculosis IspD (MpIspD) is also reported. The melting temperatures of MpIspD and BtIspD were evaluated by circular dichroism. The moderate Tm values suggest that a thermal shift assay may be feasible for future inhibitor screening. Finally, the binding affinity of CTP for BtIspD was evaluated by isothermal titration calorimetry. These structural and biophysical data will aid in the discovery of IspD inhibitors.


Asunto(s)
Burkholderia , Mycobacterium avium subsp. paratuberculosis , Difosfatos , Cristalografía por Rayos X
3.
Microbiol Resour Announc ; 13(1): e0034523, 2024 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-38038463

RESUMEN

Sphingomonadaceae are common membrane colonizers and biofilm formers. As part of our studies on long-term genetic changes in drinking water biofilm species, we report the draft genome sequence of Sphingomonas strain Sph5, isolated from a tap water filtration membrane. The isolate was determined as Sphingomonas paucimobilis through whole genome sequencing and de novo assembly.

4.
Emerg Infect Dis ; 27(10): 2718-2720, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34545803

RESUMEN

Genomic surveillance can provide early insights into new circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. While conducting genomic surveillance (1,663 cases) from December 2020-April 2021 in Arizona, USA, we detected an emergent E484K-harboring variant, B.1.243.1. This finding demonstrates the importance of real-time SARS-CoV-2 surveillance to better inform public health responses.


Asunto(s)
COVID-19 , SARS-CoV-2 , Arizona/epidemiología , Genómica , Humanos , Salud Pública
5.
Bioorg Med Chem Lett ; 48: 128273, 2021 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-34298132

RESUMEN

The enzyme 2-methylerythritol 2,4-cyclodiphosphate synthase, IspF, is essential for the biosynthesis of isoprenoids in most bacteria, some eukaryotic parasites, and the plastids of plant cells. The development of inhibitors that target IspF may lead to novel classes of anti-infective agents or herbicides. Enantiomers of tryptophan hydroxamate were synthesized and evaluated for binding to Burkholderia pseudomallei (Bp) IspF. The L-isomer possessed the highest potency, binding BpIspF with a KD of 36 µM and inhibited BpIspF activity 55% at 120 µM. The high-resolution crystal structure of the L-tryptophan hydroxamate (3)/BpIspF complex revealed a non-traditional mode of hydroxamate binding where the ligand interacts with the active site zinc ion through the primary amine. In addition, two hydrogen bonds are formed with active site groups, and the indole group is buried within the hydrophobic pocket composed of side chains from the 60 s/70 s loop. Along with the co-crystal structure, STD NMR studies suggest the methylene group and indole ring are potential positions for optimization to enhance binding potency.


Asunto(s)
Proteínas Bacterianas/antagonistas & inhibidores , Burkholderia pseudomallei/enzimología , Inhibidores Enzimáticos/farmacología , Triptófano/análogos & derivados , Proteínas Bacterianas/metabolismo , Sitios de Unión/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Triptófano/síntesis química , Triptófano/química , Triptófano/farmacología
6.
Bioorg Med Chem Lett ; 29(20): 126660, 2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31521478

RESUMEN

Enzymes in the methylerythritol phosphate pathway make attractive targets for antibacterial activity due to their importance in isoprenoid biosynthesis and the absence of the pathway in mammals. The fifth enzyme in the pathway, 2-C-methyl-d-erythritol-2,4-cyclodiphosphate synthase (IspF), contains a catalytically important zinc ion in the active site. A series of de novo designed compounds containing a zinc binding group was synthesized and evaluated for antibacterial activity and interaction with IspF from Burkholderia pseudomallei, the causative agent of Whitmore's disease. The series demonstrated antibacterial activity as well as protein stabilization in fluorescence-based thermal shift assays. Finally, the binding of one compound to Burkholderia pseudomallei IspF was evaluated through group epitope mapping by saturation transfer difference NMR.


Asunto(s)
Antibacterianos/química , Proteínas Bacterianas/biosíntesis , Burkholderia pseudomallei/enzimología , Eritritol/análogos & derivados , Liasas de Fósforo-Oxígeno/química , Liasas de Fósforo-Oxígeno/metabolismo , Pirimidinas/química , Catálisis , Dominio Catalítico , Cristalografía por Rayos X , Eritritol/biosíntesis , Humanos , Cinética , Estructura Molecular , Unión Proteica , Transducción de Señal , Zinc/química
7.
Bioorg Med Chem Lett ; 23(24): 6860-3, 2013 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-24157367

RESUMEN

Published biological data suggest that the methyl erythritol phosphate (MEP) pathway, a non-mevalonate isoprenoid biosynthetic pathway, is essential for certain bacteria and other infectious disease organisms. One highly conserved enzyme in the MEP pathway is 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF). Fragment-bound complexes of IspF from Burkholderia pseudomallei were used to design and synthesize a series of molecules linking the cytidine moiety to different zinc pocket fragment binders. Testing by surface plasmon resonance (SPR) found one molecule in the series to possess binding affinity equal to that of cytidine diphosphate, despite lacking any metal-coordinating phosphate groups. Close inspection of the SPR data suggest different binding stoichiometries between IspF and test compounds. Crystallographic analysis shows important variations between the binding mode of one synthesized compound and the pose of the bound fragment from which it was designed. The binding modes of these molecules add to our structural knowledge base for IspF and suggest future refinements in this compound series.


Asunto(s)
Proteínas Bacterianas/antagonistas & inhibidores , Burkholderia/efectos de los fármacos , Burkholderia/metabolismo , Citidina/análogos & derivados , Citidina/farmacología , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Citidina/metabolismo , Simulación del Acoplamiento Molecular , Unión Proteica , Estructura Terciaria de Proteína , Resonancia por Plasmón de Superficie
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