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000904319 0247_ $$2doi$$a10.1016/j.jmb.2020.166763
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000904319 1001_ $$0P:(DE-HGF)0$$aVaraksa, Tatsiana$$b0
000904319 245__ $$aMetabolic Fate of Human Immunoactive Sterols in Mycobacterium tuberculosis
000904319 260__ $$aAmsterdam [u.a.]$$bElsevier$$c2021
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000904319 520__ $$aMycobacterium tuberculosis (Mtb) infection is among top ten causes of death worldwide, and the number of drug-resistant strains is increasing. The direct interception of human immune signaling molecules by Mtb remains elusive, limiting drug discovery. Oxysterols and secosteroids regulate both innate and adaptive immune responses. Here we report a functional, structural, and bioinformatics study of Mtb enzymes initiating cholesterol catabolism and demonstrated their interrelation with human immunity. We show that these enzymes metabolize human immune oxysterol messengers. Rv2266 – the most potent among them – can also metabolize vitamin D3 (VD3) derivatives. High-resolution structures show common patterns of sterols binding and reveal a site for oxidative attack during catalysis. Finally, we designed a compound that binds and inhibits three studied proteins. The compound shows activity against Mtb H37Rv residing in macrophages. Our findings contribute to molecular understanding of suppression of immunity and suggest that Mtb has its own transformation system resembling the human phase I drug-metabolizing system.
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000904319 7001_ $$0P:(DE-HGF)0$$aBukhdruker, Sergey$$b1
000904319 7001_ $$0P:(DE-HGF)0$$aGrabovec, Irina$$b2
000904319 7001_ $$0P:(DE-HGF)0$$aMarin, Egor$$b3
000904319 7001_ $$0P:(DE-HGF)0$$aKavaleuski, Anton$$b4
000904319 7001_ $$0P:(DE-HGF)0$$aGusach, Anastasiia$$b5
000904319 7001_ $$aKovalev, Kirill$$b6
000904319 7001_ $$aMaslov, Ivan$$b7
000904319 7001_ $$aLuginina, Aleksandra$$b8
000904319 7001_ $$0P:(DE-Juel1)176570$$aZabelskii, Dmitrii$$b9$$ufzj
000904319 7001_ $$aAstashkin, Roman$$b10
000904319 7001_ $$aShevtsov, Mikhail$$b11
000904319 7001_ $$aSmolskaya, Sviatlana$$b12
000904319 7001_ $$aKavaleuskaya, Anna$$b13
000904319 7001_ $$aShabunya, Polina$$b14
000904319 7001_ $$aBaranovsky, Alexander$$b15
000904319 7001_ $$aDolgopalets, Vladimir$$b16
000904319 7001_ $$aCharnou, Yury$$b17
000904319 7001_ $$aSavachka, Aleh$$b18
000904319 7001_ $$aLitvinovskaya, Raisa$$b19
000904319 7001_ $$aHurski, Alaksiej$$b20
000904319 7001_ $$aShevchenko, Evgeny$$b21
000904319 7001_ $$aRogachev, Andrey$$b22
000904319 7001_ $$aMishin, Alexey$$b23
000904319 7001_ $$0P:(DE-Juel1)131964$$aGordeliy, Valentin$$b24$$ufzj
000904319 7001_ $$aGabrielian, Andrei$$b25
000904319 7001_ $$aHurt, Darrell E.$$b26
000904319 7001_ $$aNikonenko, Boris$$b27
000904319 7001_ $$aMajorov, Konstantin$$b28
000904319 7001_ $$aApt, Alexander$$b29
000904319 7001_ $$aRosenthal, Alex$$b30
000904319 7001_ $$aGilep, Andrei$$b31
000904319 7001_ $$0P:(DE-Juel1)191126$$aBorshchevskiy, Valentin$$b32$$eCorresponding author
000904319 7001_ $$0P:(DE-HGF)0$$aStrushkevich, Natallia$$b33$$eCorresponding author
000904319 773__ $$0PERI:(DE-600)1355192-9$$a10.1016/j.jmb.2020.166763$$gVol. 433, no. 4, p. 166763 -$$n4$$p166763 -$$tJournal of molecular biology$$v433$$x0022-2836$$y2021
000904319 8564_ $$uhttps://juser.fz-juelich.de/record/904319/files/2020.07.07.192294v1.full.pdf$$yOpenAccess
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