Progesterone Receptor Ligand Binding Pocket Flexibility:  Crystal Structures of the Norethindrone and Mometasone Furoate Complexes

2004 ◽  
Vol 47 (13) ◽  
pp. 3381-3387 ◽  
Author(s):  
Kevin P. Madauss ◽  
Su-Jun Deng ◽  
Robert J. H. Austin ◽  
Millard H. Lambert ◽  
Iain McLay ◽  
...  
Keyword(s):  
Progesterone Receptor ◽  
Ligand Binding ◽  
Crystal Structures ◽  
Binding Pocket ◽  
Mometasone Furoate ◽  
Receptor Ligand ◽  
Ligand Binding Pocket

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

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.

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 Suramin Targets the Conserved Ligand-Binding Pocket of Human Raf1 Kinase Inhibitory Protein

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1151
Author(s):  
Chenyun Guo ◽  
Zhihua Wu ◽  
Weiliang Lin ◽  
Hao Xu ◽  
Ting Chang ◽  
...  
Keyword(s):  
Side Effects ◽  
Ligand Binding ◽  
Mapk Pathway ◽  
Regulatory Protein ◽  
Therapeutic Index ◽  
Binding Pocket ◽  
Biological Macromolecules ◽  
Inhibitory Protein ◽  
Ligand Binding Pocket ◽  
Raf1 Kinase

Suramin was initially used to treat African sleeping sickness and has been clinically tested to treat human cancers and HIV infection in the recent years. However, the therapeutic index is low with numerous clinical side-effects, attributed to its diverse interactions with multiple biological macromolecules. Here, we report a novel binding target of suramin, human Raf1 kinase inhibitory protein (hRKIP), which is an important regulatory protein involved in the Ras/Raf1/MEK/ERK (MAPK) signal pathway. Biolayer interference technology showed that suramin had an intermediate affinity for binding hRKIP with a dissociation constant of 23.8 µM. Both nuclear magnetic resonance technology and molecular docking analysis revealed that suramin bound to the conserved ligand-binding pocket of hRKIP, and that residues K113, W173, and Y181 play crucial roles in hRKIP binding suramin. Furthermore, suramin treatment at 160 µM could profoundly increase the ERK phosphorylation level by around 3 times. Our results indicate that suramin binds to hRKIP and prevents hRKIP from binding with hRaf1, thus promoting the MAPK pathway. This work is beneficial to both mechanistically understanding the side-effects of suramin and efficiently improving the clinical applications of suramin.

scholarly journals Ligands with poly-fluorophenyl moieties promote a local structural rearrangement in the Spinach2 and Broccoli aptamers that increases ligand affinities

2021 ◽  
Author(s):  
Sharif Anisuzzaman ◽  
Ivan M Geraskin ◽  
Muslum Ilgu ◽  
Lee Bendickson ◽  
George A Kraus ◽  
...  
Keyword(s):  
Nucleic Acids ◽  
Ligand Binding ◽  
Small Molecule ◽  
Binding Pocket ◽  
Structural Rearrangement ◽  
Structural Reorganization ◽  
Ligand Binding Pocket ◽  
Rna Remodeling ◽  
Small Molecule Ligands ◽  
Target Molecules

The interaction of nucleic acids with their molecular targets often involves structural reorganization that may traverse a complex folding landscape. With the more recent recognition that many RNAs, both coding and noncoding, may regulate cellular activities by interacting with target molecules, it becomes increasingly important to understand the means by which nucleic acids interact with their targets and how drugs might be developed that can influence critical folding transitions. We have extensively investigated the interaction of the Spinach2 and Broccoli aptamers with a library of small molecule ligands modified by various extensions from the imido nitrogen of DFHBI (3,5-difluoro-4-hydroxybenzylidene imidazolinone) that reach out from the Spinach2 ligand binding pocket. Studies of the interaction of these compounds with the aptamers revealed that poly-fluorophenyl-modified ligands initiate a slow change in aptamer affinity that takes an extended time (half-life of ~40 min) to achieve. The change in affinity appears to involve an initial disruption of the entrance to the ligand binding pocket followed by a gradual lockdown for which the most likely driving force is an interaction of the gateway adenine with a nearby 2'OH group. These results suggest that poly-fluorophenyl modifications might increase the ability of small molecule drugs to disrupt local structure and promote RNA remodeling.

Ligand binding pocket function of Drosophila USP is necessary for metamorphosis

2013 ◽  
Vol 182 ◽  
pp. 73-82 ◽  
Author(s):  
Grace Jones ◽  
Peter Teal ◽  
Vincent C. Henrich ◽  
Anna Krzywonos ◽  
Agnes Sapa ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Pocket ◽  
Ligand Binding Pocket
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