Computational analysis of the structural basis of ligand binding to the crustacean retinoid X receptor

2010 ◽  
Vol 5 (4) ◽  
pp. 317-324 ◽  
Author(s):  
G. Purna Chandra Nagaraju ◽  
G.L.V. Prasad ◽  
L. Taliaferro-Smith ◽  
B.V. Aruna ◽  
B. Reddya Naik ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Computational Analysis ◽  
Retinoid X Receptor ◽  
Structural Basis

scholarly journals Ligand binding and heterodimerization with retinoid X receptor α (RXRα) induce farnesoid X receptor (FXR) conformational changes affecting coactivator binding

2018 ◽  
Vol 293 (47) ◽  
pp. 18180-18191 ◽  
Author(s):  
Na Wang ◽  
Qingan Zou ◽  
Jinxin Xu ◽  
Jiancun Zhang ◽  
Jinsong Liu
Keyword(s):  
Ligand Binding ◽  
Nuclear Receptor ◽  
Conformational Changes ◽  
Cholesterol Metabolism ◽  
Retinoid X Receptor ◽  
Farnesoid X Receptor ◽  
Dietary Fats ◽  
Structural Basis ◽  
Biliary Cirrhosis ◽  
C Terminus

Nuclear receptor farnesoid X receptor (FXR) functions as the major bile acid sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins. Because of its central role in metabolism, FXR represents an important drug target to manage metabolic and other diseases, such as primary biliary cirrhosis and nonalcoholic steatohepatitis. FXR and nuclear receptor retinoid X receptor α (RXRα) form a heterodimer that controls the expression of numerous downstream genes. To date, the structural basis and functional consequences of the FXR/RXR heterodimer interaction have remained unclear. Herein, we present the crystal structures of the heterodimeric complex formed between the ligand-binding domains of human FXR and RXRα. We show that both FXR and RXR bind to the transcriptional coregulator steroid receptor coactivator 1 with higher affinity when they are part of the heterodimer complex than when they are in their respective monomeric states. Furthermore, structural comparisons of the FXR/RXRα heterodimers and the FXR monomers bound with different ligands indicated that both heterodimerization and ligand binding induce conformational changes in the C terminus of helix 11 in FXR that affect the stability of the coactivator binding surface and the coactivator binding in FXR. In summary, our findings shed light on the allosteric signal transduction in the FXR/RXR heterodimer, which may be utilized for future drug development targeting FXR.

scholarly journals Structural basis for Na+-sensitivity in dopamine D2 and D3 receptors

2015 ◽  
Vol 51 (41) ◽  
pp. 8618-8621 ◽  
Author(s):  
Mayako Michino ◽  
R. Benjamin Free ◽  
Trevor B. Doyle ◽  
David R. Sibley ◽  
Lei Shi
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Computational Analysis ◽  
Structural Basis ◽  
Ligand Binding Site ◽  
Binding Assays ◽  
D3 Receptors ◽  
Dopamine D2 ◽  
The Impact

To understand the structural basis for the Na+-sensitivity of ligand binding to dopamine D2-like receptors, using computational analysis in combination with binding assays, we identified interactions critical in propagating the impact of Na+on receptor conformations and on the ligand-binding site.

scholarly journals Structural Basis of Ligand Binding to UDP-Galactopyranose Mutase fromMycobacterium tuberculosisUsing Substrate and Tetrafluorinated Substrate Analogues

2015 ◽  
Vol 137 (3) ◽  
pp. 1230-1244 ◽  
Author(s):  
Karin E. van Straaten ◽  
Jijin R. A. Kuttiyatveetil ◽  
Charlotte M. Sevrain ◽  
Sydney A. Villaume ◽  
Jesús Jiménez-Barbero ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Structural Basis ◽  
Substrate Analogues

scholarly journals Human Group C Rotavirus VP8*s Recognize Type A Histo-Blood Group Antigens as Ligands

2018 ◽  
Vol 92 (11) ◽  
Author(s):  
Xiaoman Sun ◽  
Lihong Wang ◽  
Jianxun Qi ◽  
Dandi Li ◽  
Mengxuan Wang ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Blood Group ◽  
Specific Interaction ◽  
Type A ◽  
Host Susceptibility ◽  
Structural Basis ◽  
Receptor Interaction ◽  
Blood Group Antigens ◽  
Group Species

ABSTRACTGroup/species C rotaviruses (RVCs) have been identified as important pathogens of acute gastroenteritis (AGE) in children, family-based outbreaks, as well as animal infections. However, little is known regarding their host-specific interaction, infection, and pathogenesis. In this study, we performed serial studies to characterize the function and structural features of a human G4P[2] RVC VP8* that is responsible for the host receptor interaction. Glycan microarrays demonstrated that the human RVC VP8* recognizes type A histo-blood group antigens (HBGAs), which was confirmed by synthetic glycan-/saliva-based binding assays and hemagglutination of red blood cells, establishing a paradigm of RVC VP8*-glycan interactions. Furthermore, the high-resolution crystal structure of the human RVC VP8* was solved, showing a typical galectin-like structure consisting of two β-sheets but with significant differences from cogent proteins of group A rotaviruses (RVAs). The VP8* in complex with a type A trisaccharide displays a novel ligand binding site that consists of a particular set of amino acid residues of the C-D, G-H, and K-L loops. RVC VP8* interacts with type A HBGAs through a unique mechanism compared with that used by RVAs. Our findings shed light on the host-virus interaction and the coevolution of RVCs and will facilitate the development of specific antivirals and vaccines.IMPORTANCEGroup/species C rotaviruses (RVCs), members ofReoviridaefamily, infect both humans and animals, but our knowledge about the host factors that control host susceptibility and specificity is rudimentary. In this work, we characterized the glycan binding specificity and structural basis of a human RVC that recognizes type A HBGAs. We found that human RVC VP8*, the rotavirus host ligand binding domain that shares only ∼15% homology with the VP8* domains of RVAs, recognizes type A HBGA at an as-yet-unknown glycan binding site through a mechanism distinct from that used by RVAs. Our new advancements provide insights into RVC-cell attachment, the critical step of virus infection, which will in turn help the development of control and prevention strategies against RVs.

scholarly journals Ancient and conserved functional interplay between Bcl-2 family proteins in the mitochondrial pathway of apoptosis

2020 ◽  
Vol 6 (40) ◽  
pp. eabc4149 ◽  
Author(s):  
Nikolay Popgeorgiev ◽  
Jaison D Sa ◽  
Lea Jabbour ◽  
Suresh Banjara ◽  
Trang Thi Minh Nguyen ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Ligand Binding ◽  
Cancer Cells ◽  
Mitochondrial Pathway ◽  
Structural Basis ◽  
Mitochondrial Outer Membrane ◽  
Chemotherapy Treatment ◽  
Trichoplax Adhaerens ◽  
Binding Groove

In metazoans, Bcl-2 family proteins are major regulators of mitochondrially mediated apoptosis; however, their evolution remains poorly understood. Here, we describe the molecular characterization of the four members of the Bcl-2 family in the most primitive metazoan, Trichoplax adhaerens. All four trBcl-2 homologs are multimotif Bcl-2 group, with trBcl-2L1 and trBcl-2L2 being highly divergent antiapoptotic Bcl-2 members, whereas trBcl-2L3 and trBcl-2L4 are homologs of proapoptotic Bax and Bak, respectively. trBax expression permeabilizes the mitochondrial outer membrane, while trBak operates as a BH3-only sensitizer repressing antiapoptotic activities of trBcl-2L1 and trBcl-2L2. The crystal structure of a trBcl-2L2:trBak BH3 complex reveals that trBcl-2L2 uses the canonical Bcl-2 ligand binding groove to sequester trBak BH3, indicating that the structural basis for apoptosis control is conserved from T. adhaerens to mammals. Finally, we demonstrate that both trBax and trBak BH3 peptides bind selectively to human Bcl-2 homologs to sensitize cancer cells to chemotherapy treatment.

scholarly journals Structural Basis of Cooperative Ligand Binding by the Glycine Riboswitch

2011 ◽  
Vol 18 (3) ◽  
pp. 293-298 ◽  
Author(s):  
Ethan B. Butler ◽  
Yong Xiong ◽  
Jimin Wang ◽  
Scott A. Strobel
Keyword(s):  
Ligand Binding ◽  
Structural Basis

scholarly journals A structural basis for how ligand binding site changes can allosterically regulate GPCR signaling and engender functional selectivity

2020 ◽  
Vol 13 (617) ◽  
pp. eaaw5885 ◽  
Author(s):  
Marta Sanchez-Soto ◽  
Ravi Kumar Verma ◽  
Blair K. A. Willette ◽  
Elizabeth C. Gonye ◽  
Annah M. Moore ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
G Protein ◽  
Structural Basis ◽  
Protein Signaling ◽  
Ligand Binding Site ◽  
Intracellular Loop ◽  
Gpcr Signaling ◽  
Biased Signaling ◽  
Dynamics Simulations

Signaling bias is the propensity for some agonists to preferentially stimulate G protein–coupled receptor (GPCR) signaling through one intracellular pathway versus another. We previously identified a G protein–biased agonist of the D2 dopamine receptor (D2R) that results in impaired β-arrestin recruitment. This signaling bias was predicted to arise from unique interactions of the ligand with a hydrophobic pocket at the interface of the second extracellular loop and fifth transmembrane segment of the D2R. Here, we showed that residue Phe189 within this pocket (position 5.38 using Ballesteros-Weinstein numbering) functions as a microswitch for regulating receptor interactions with β-arrestin. This residue is relatively conserved among class A GPCRs, and analogous mutations within other GPCRs similarly impaired β-arrestin recruitment while maintaining G protein signaling. To investigate the mechanism of this signaling bias, we used an active-state structure of the β2-adrenergic receptor (β2R) to build β2R-WT and β2R-Y1995.38A models in complex with the full β2R agonist BI-167107 for molecular dynamics simulations. These analyses identified conformational rearrangements in β2R-Y1995.38A that propagated from the extracellular ligand binding site to the intracellular surface, resulting in a modified orientation of the second intracellular loop in β2R-Y1995.38A, which is predicted to affect its interactions with β-arrestin. Our findings provide a structural basis for how ligand binding site alterations can allosterically affect GPCR-transducer interactions and result in biased signaling.

Structural aspects of agonism and antagonism in the oestrogen receptor

2000 ◽  
Vol 28 (4) ◽  
pp. 396-400 ◽  
Author(s):  
A. C. W. Pike ◽  
A. M. Brzozowski ◽  
J. Walton ◽  
R. E. Hubbard ◽  
T. Bonn ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Oestrogen Receptor ◽  
Three Dimensional ◽  
Receptor Activation ◽  
Structural Basis ◽  
Diverse Range ◽  
Antagonist Action ◽  
Receptor Agonists And Antagonists ◽  
Insight Into ◽  
Structural Aspects

We have determined the three-dimensional structures of both α- and β-forms of the ligand-binding domain of the oestrogen receptor (ER) in complexes with a range of receptor agonists and antagonists. Here, we summarize how these structures provide both an understanding of the ER's distinctive pharmacophore and a rationale for its ability to bind a diverse range of chemically distinct compounds. In addition, these studies provide a unique insight into the mechanisms that underlie receptor activation, as well as providing a structural basis for the antagonist action of molecules, such as raloxifene.

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