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Sökning: L773:1860 7179 OR L773:1860 7187 > When Two Become One :

When Two Become One : Conformational Changes in FXR/RXR Heterodimers Bound to Steroidal Antagonists

Diaz-Holguin, Alejandro (författare)
Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio 70211, Finland.
Rashidian, Azam (författare)
Eberhard Karls Univ Tubingen, Inst Pharm, Pharmaceut Med Chem, Morgenstelle 8, D-72076 Tubingen, Germany.;Eberhard Karls Univ Tubingen, Tubingen Ctr Acad Drug Discovery & Dev TuCAD2, Morgenstelle 8, D-72076 Tubingen, Germany.;Univ Hosp Tubingen, Dept Internal Med 8, Otfried Muller Str 14, D-72076 Tubingen, Germany.
Pijnenburg, Dirk (författare)
PamGene Int BV, Wolvenhoek 10, NL-5211 HH Shertogenbosch, Netherlands.
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Monteiro Ferreira, Glaucio (författare)
Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, Ave Prof Lineu Prestes 580, BR-05508000 Sao Paulo, Brazil.
Stefela, Alzbeta (författare)
Charles Univ Prague, Dept Pharmacol & Toxicol, Heyrovskeho 1203, Hradec Kralove 50005, Czech Republic.
Kaspar, Miroslav (författare)
Czech Acad Sci, Inst Organ Chem & Biochem, Flemingovo Namesti 542-2, Prague 16000, Czech Republic.;Charles Univ Prague, Fac Sci, Albertov 6, Prague 12843 2, Czech Republic.
Kudova, Eva (författare)
Czech Acad Sci, Inst Organ Chem & Biochem, Flemingovo Namesti 542-2, Prague 16000, Czech Republic.
Poso, Antti (författare)
Eberhard Karls Univ Tubingen, Inst Pharm, Pharmaceut Med Chem, Morgenstelle 8, D-72076 Tubingen, Germany.;Eberhard Karls Univ Tubingen, Tubingen Ctr Acad Drug Discovery & Dev TuCAD2, Morgenstelle 8, D-72076 Tubingen, Germany.;Univ Hosp Tubingen, Dept Internal Med 8, Otfried Muller Str 14, D-72076 Tubingen, Germany.;Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio 70211, Finland.
van Beuningen, Rinie (författare)
PamGene Int BV, Wolvenhoek 10, NL-5211 HH Shertogenbosch, Netherlands.
Pavek, Petr (författare)
Charles Univ Prague, Dept Pharmacol & Toxicol, Heyrovskeho 1203, Hradec Kralove 50005, Czech Republic.
Kronenberger, Thales (författare)
Eberhard Karls Univ Tubingen, Inst Pharm, Pharmaceut Med Chem, Morgenstelle 8, D-72076 Tubingen, Germany.;Eberhard Karls Univ Tubingen, Tubingen Ctr Acad Drug Discovery & Dev TuCAD2, Morgenstelle 8, D-72076 Tubingen, Germany.;Univ Hosp Tubingen, Dept Internal Med 8, Otfried Muller Str 14, D-72076 Tubingen, Germany.;Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio 70211, Finland.
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Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio 70211, Finland Eberhard Karls Univ Tubingen, Inst Pharm, Pharmaceut Med Chem, Morgenstelle 8, D-72076 Tubingen, Germany.;Eberhard Karls Univ Tubingen, Tubingen Ctr Acad Drug Discovery & Dev TuCAD2, Morgenstelle 8, D-72076 Tubingen, Germany.;Univ Hosp Tubingen, Dept Internal Med 8, Otfried Muller Str 14, D-72076 Tubingen, Germany. (creator_code:org_t)
2022-11-30
2023
Engelska.
Ingår i: ChemMedChem. - : John Wiley & Sons. - 1860-7179 .- 1860-7187. ; 18:4
Relaterad länk:
https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
https://urn.kb.se/re...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • Farnesoid X receptor (FXR) is a nuclear receptor with an essential role in regulating bile acid synthesis and cholesterol homeostasis. FXR activation by agonists is explained by an alpha AF-2-trapping mechanism; however, antagonism mechanisms are diverse. We discuss microsecond molecular dynamics (MD) simulations investigating our recently reported FXR antagonists 2a and 2 h. We study the antagonist-induced conformational changes in the FXR ligand-binding domain, when compared to the synthetic (GW4064) or steroidal (chenodeoxycholic acid, CDCA) FXR agonists in the FXR monomer or FXR/RXR heterodimer r, and in the presence and absence of the coactivator. Our MD data suggest ligand-specific influence on conformations of different FXR-LBD regions, including the alpha 5/alpha 6 region, alpha AF-2, and alpha 9-11. Changes in the heterodimerization interface induced by antagonists seem to be associated with alpha AF-2 destabilization, which prevents both co-activator and co-repressor recruitment. Our results provide new insights into the conformational behaviour of FXR, suggesting that FXR antagonism/agonism shift requires a deeper assessment than originally proposed by crystal structures.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)

Nyckelord

bile acids
molecular dynamics simulations
nuclear receptors
farnesoid X receptor

Publikations- och innehållstyp

ref (ämneskategori)
art (ämneskategori)

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