The Promiscuity of Allosteric Regulation of Nuclear Receptors by Retinoid X Receptor.
The promiscuous protein retinoid X receptor (RXR) displays essential allosteric regulation of several members in the nuclear hormone receptor superfamily via heterodimerization and (anti)cooperative binding of cognate ligands. Here, the structural basis of the positive allostery of RXR and constitutive androstane receptor (CAR) is revealed. In contrast, a similar computational approach had previously revealed the mechanism for negative allostery in the complex of RXR and thyroid receptor (TR). By comparing the positive and negative allostery of RXR complexed with CAR and TR respectively, we reported the promiscuous allosteric control involving RXR. We characterize the allosteric mechanism by expressing the correlated dynamics of selected residue-residue contacts which was extracted from atomistic molecular dynamics simulation and statistical analysis. While the same set of residues in the binding pocket of RXR may initiate the residue-residue interaction network, RXR uses largely different sets of contacts (only about one-third identical) and allosteric modes to regulate TR and CAR. The promiscuity of RXR control may originate from multiple factors, including (1) the frustrated fit of cognate ligand 9c to the RXR binding pocket and (2) the different ligand-binding features of TR (loose) versus CAR (tight) to their corresponding cognate ligands.
Alexander K
AK
Clark
J Heath
JH
Wilder
Aaron W
AW
Grayson
UT-ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37830, United States.
Quentin R
QR
Johnson
UT-ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37830, United States.
Richard J
RJ
Lindsay
Institute of Chemistry, University of the Philippines Diliman , Quezon City, Philippines.
Ricky B
RB
Nellas
Elias J
EJ
Fernandez
UT-ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37830, United States.
Tongye
T
Shen
D000494:Allosteric Regulation; D000818:Animals; D030161:Avian Proteins / Q000378:metabolism; D001665:Binding Sites; D002645:Chickens; D000090702:Constitutive Androstane Receptor; D006801:Humans; D051379:Mice; D056004:Molecular Dynamics Simulation; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism*
D030161:Avian Proteins; D000090702:Constitutive Androstane Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors