When Two Become One: Conformational Changes in FXR/RXR Heterodimers Bound to Steroidal Antagonists
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F23%3A00565349" target="_blank" >RIV/61388963:_____/23:00565349 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11160/23:10472233 RIV/00216208:11310/23:10472233
Result on the web
<a href="https://doi.org/10.1002/cmdc.202200556" target="_blank" >https://doi.org/10.1002/cmdc.202200556</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/cmdc.202200556" target="_blank" >10.1002/cmdc.202200556</a>
Alternative languages
Result language
angličtina
Original language name
When Two Become One: Conformational Changes in FXR/RXR Heterodimers Bound to Steroidal Antagonists
Original language description
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 αAF-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 α5/α6 region, αAF-2, and α9-11. Changes in the heterodimerization interface induced by antagonists seem to be associated with αAF-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.
Czech name
—
Czech description
—
Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
10401 - Organic chemistry
Result continuities
Project
—
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2023
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
ChemMedChem
ISSN
1860-7179
e-ISSN
1860-7187
Volume of the periodical
18
Issue of the periodical within the volume
4
Country of publishing house
DE - GERMANY
Number of pages
15
Pages from-to
e202200556
UT code for WoS article
000892537500001
EID of the result in the Scopus database
2-s2.0-85143169860