scholarly journals Correction to ‘Evolutionary diversification of retinoic acid receptor ligand-binding pocket structure by molecular tinkering'

2016 ◽  
Vol 3 (12) ◽  
pp. 160895
Author(s):  
Julianan Gutierrez-Mazariegos ◽  
Eswar Kumar Nadendla ◽  
Romain A. Studer ◽  
Susana Alvarez ◽  
Angel R. de Lera ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Ligand Binding ◽  
Retinoic Acid Receptor ◽  
Binding Pocket ◽  
Receptor Ligand ◽  
Ligand Binding Pocket ◽  
Acid Receptor ◽  
Evolutionary Diversification

scholarly journals Serine 232 and Methionine 272 Define the Ligand Binding Pocket in Retinoic Acid Receptor Subtypes

1998 ◽  
Vol 273 (6) ◽  
pp. 3490-3495 ◽  
Author(s):  
Jacek Ostrowski ◽  
Thor Roalsvig ◽  
Laura Hammer ◽  
Anne Marinier ◽  
John E. Starrett ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Ligand Binding ◽  
Retinoic Acid Receptor ◽  
Binding Pocket ◽  
Receptor Subtypes ◽  
Ligand Binding Pocket ◽  
Acid Receptor

scholarly journals Identification of Sulfhydryl-modified Cysteine Residues in the Ligand Binding Pocket of Retinoic Acid Receptor β

1997 ◽  
Vol 272 (2) ◽  
pp. 746-753 ◽  
Author(s):  
Christopher L. Wolfgang ◽  
Zhen-ping Zhang ◽  
Jerome L. Gabriel ◽  
Ronald A. Pieringer ◽  
Kenneth J. Soprano ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Ligand Binding ◽  
Retinoic Acid Receptor ◽  
Binding Pocket ◽  
Cysteine Residues ◽  
Ligand Binding Pocket ◽  
Acid Receptor

Expression of human all-trans-retinoic acid receptor β and its ligand-binding domain in Escherichia coli

1995 ◽  
Vol 308 (1) ◽  
pp. 353-359 ◽  
Author(s):  
M Berggren Söderlund ◽  
G Johannesson ◽  
G Fex
Keyword(s):  
Escherichia Coli ◽  
Retinoic Acid ◽  
Ligand Binding ◽  
Retinoic Acid Receptor ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Acid Receptor ◽  
Recombinant Receptors ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

all-trans-Retinoic acid, one of the hormonally active derivatives of vitamin A, occurs physiologically in plasma at a concentration below 10 nmol/l. The methods currently used for its quantification are based on HPLC, need about 1 ml of serum, are relatively laborious and thus not well suited for mass analysis. The affinity and specificity of retinoic acid receptors for all-trans-retinoic acid encouraged us to express both the entire human retinoic acid receptor beta (RAR-beta) and two versions of its retinoic acid-binding domain in Escherichia coli in the hope that these recombinant proteins might be used as binders in a ligand-binding assay for all-trans-retinoic acid. The recombinant receptors, the whole receptor [RAR-beta-(V7-Q448)], corresponding to domains A-F, and the ligand-binding domain [RAR-beta-(E149-Q448)], corresponding to domains D-F, were expressed in the vector pET 3d/BL21 (DE3) as inclusion bodies, solubilized with guanidinium chloride, renatured and purified by ion-exchange chromatography. RAR-beta-(P193-Q448), corresponding to domains E-F, was expressed in the vector pET 3d/BL21(DE3)pLysS, and purified by reversed-phase chromatography. Under non-denaturing conditions, the expressed whole receptor [RAR-beta-(V7-Q448)] and the D-F construct (RAR-beta-(E149-Q448)] behaved chromatographically as monomeric proteins whereas the E-F construct [RAR-beta-(P193-Q448)] had a strong tendency to aggregate. RAR-beta-(V7-Q448) and RAR-beta-(E149-Q448) had similar Kd values for all-trans-retinoic acid (1.4 and 0.6 nmol/l respectively) whereas RAR-beta-(P193-Q448) bound all-trans-retinoic acid less avidly (Kd 9.6 nmol/l). 9-cis-Retinoic acid bound to RAR-beta-(E149-Q448) and RAR-beta-(V7-Q448) as avidly as all-trans-retinoic acid. Competition experiments showed weak or no binding of 4-oxo-all-trans-retinoic acid, 4-oxo-13-cis-retinoic acid, 13-cis-retinoic acid, acitretin and retinol by RAR-beta-(E149-Q448).

scholarly journals SUN-LB138 Dynamic Structural Model of Testosterone Entry Into the Unliganded Androgen Receptor

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Irina Krylova ◽  
Fred J Schaufele ◽  
Christophe Guilbert
Keyword(s):  
Amino Acids ◽  
Androgen Receptor ◽  
Ligand Binding ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Binding Pocket ◽  
Binding Domain ◽  
Receptor Ligand ◽  
Ligand Binding Pocket ◽  
Crystallographic Structures

Abstract Background: Crystallographic structures of nuclear receptor ligand binding domains provide a static model of a receptor stably wrapped around an internalized ligand. Understanding the dynamics of a receptor at different stages of ligand binding has been hampered by the paucity of crystal structures for unliganded nuclear receptors. Molecular dynamic models have been constructed for some nuclear receptors to fill that void. Methods: The molecular simulation docking program MORDOR (MOlecular Recognition with a Driven dynamics OptimizeR)(1) was used to study the structural dynamics of the androgen receptor ligand binding domain (AR LBD) modeled from the static structure of the AR LBD bound to testosterone (T) (PDB ID: 2AM9). The goals of the study were to understand a) the dynamic interaction of the T in its binding pocket, b) AR LBD structural flexibilities that permit T entry/exit from the binding pocket and c) a model of the unliganded AR LBD. Results: Modeling AR LBD structure flexibility over time revealed possible alternative dynamic structures, including those without ligand, overlaid against the canonical nuclear receptor structure. The model dynamically tracks the structural changes as a ligand enters into the ligand binding domain and nestles into the ligand binding pocket. The model predicted the appearance of alpha helices within the AR LBD that transiently fold/unfold during the ligand entry phases. Once in the pocket, the ligand itself remains very dynamic in a still flexible pocket. The model predicted also AR LBD amino acids that sequentially interact with the ligand during its dynamic entry into the AR LBD. Intriguingly, those AR amino acids include those mutated in castration-resistant prostate tumors that continue to grow during androgen suppression therapy. Functional studies showed those mutant ARs had a primary consequence of enhancing response to lower level T, and other androgens, consistent with their role in creating a higher affinity AR that can scavenge low-level androgens in an androgen-suppressed patient. Conclusions: The molecular model of T binding to the AR LBD suggests a degree of structural dynamism not evident in the crystallographic structures commonly associated with nuclear receptors. Some AR mutations activating prostate tumor growth may do so by impacting androgen entry/exit, rather than by altering androgen fit into the ligand binding pocket. Reference: (1) Guilbert C, James TL (2008) J Chem Inf Model. 2008 48(6): 1257-1268. doi: 10.1021/ci8000327

ChemInform Abstract: Synthesis and Characterization of a Highly Potent and Selective Isotopically Labeled Retinoic Acid Receptor Ligand, ALRT1550.

ChemInform ◽  
2010 ◽  
Vol 29 (27) ◽  
pp. no-no
Author(s):  
Y. L. BENNANI ◽  
K. S. MARRON ◽  
D. E. MAIS ◽  
K. FLATTEN ◽  
A. M. NADZAN ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Synthesis And Characterization ◽  
Receptor Ligand ◽  
Acid Receptor

Synthesis and Characterization of a Highly Potent and Selective Isotopically Labeled Retinoic Acid Receptor Ligand, ALRT1550

1998 ◽  
Vol 63 (3) ◽  
pp. 543-550 ◽  
Author(s):  
Youssef L. Bennani ◽  
Kristin S. Marron ◽  
Dale E. Mais ◽  
Karen Flatten ◽  
Alex M. Nadzan ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Synthesis And Characterization ◽  
Receptor Ligand ◽  
Acid Receptor

scholarly journals Doubling the Size of the Glucocorticoid Receptor Ligand Binding Pocket by Deacylcortivazol

2007 ◽  
Vol 28 (6) ◽  
pp. 1915-1923 ◽  
Author(s):  
Kelly Suino-Powell ◽  
Yong Xu ◽  
Chenghai Zhang ◽  
Yong-guang Tao ◽  
W. David Tolbert ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Ligand Binding ◽  
Binding Pocket ◽  
Affinity Binding ◽  
Receptor Ligand ◽  
Ligand Binding Pocket ◽  
Steroid Receptor Coactivator ◽  
High Affinity ◽  
Binding Domains ◽  
Lxxll Motif

ABSTRACT A common feature of nuclear receptor ligand binding domains (LBD) is a helical sandwich fold that nests a ligand binding pocket within the bottom half of the domain. Here we report that the ligand pocket of glucocorticoid receptor (GR) can be continuously extended into the top half of the LBD by binding to deacylcortivazol (DAC), an extremely potent glucocorticoid. It has been puzzling for decades why DAC, which contains a phenylpyrazole replacement at the conserved 3-ketone of steroid hormones that are normally required for activation of their cognate receptors, is a potent GR activator. The crystal structure of the GR LBD bound to DAC and the fourth LXXLL motif of steroid receptor coactivator 1 reveals that the GR ligand binding pocket is expanded to a size of 1,070 Å3, effectively doubling the size of the GR dexamethasone-binding pocket of 540 Å3 and yet leaving the structure of the coactivator binding site intact. DAC occupies only ∼50% of the space of the pocket but makes intricate interactions with the receptor around the phenylpyrazole group that accounts for the high-affinity binding of DAC. The dramatic expansion of the DAC-binding pocket thus highlights the conformational adaptability of GR to ligand binding. The new structure also allows docking of various nonsteroidal ligands that cannot be fitted into the previous structures, thus providing a new rational template for drug discovery of steroidal and nonsteroidal glucocorticoids that can be specifically designed to reach the unoccupied space of the expanded pocket.

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