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.

scholarly journals Structural Basis for Ligand Binding and Processivity in Cellobiohydrolase Cel6A from Humicola insolens

Structure ◽  
2003 ◽  
Vol 11 (7) ◽  
pp. 855-864 ◽  
Author(s):  
Annabelle Varrot ◽  
Torben P. Frandsen ◽  
Ingemar von Ossowski ◽  
Viviane Boyer ◽  
Sylvain Cottaz ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Structural Basis ◽  
Humicola Insolens

scholarly journals Structural basis for ligand binding to the guanidine-II riboswitch

RNA ◽  
2017 ◽  
Vol 23 (9) ◽  
pp. 1338-1343 ◽  
Author(s):  
Caroline W. Reiss ◽  
Scott A. Strobel
Keyword(s):  
Ligand Binding ◽  
Structural Basis

scholarly journals Structural Basis for the Cell-specific Activities of the NGFI-B and the Nurr1 Ligand-binding Domain

2005 ◽  
Vol 280 (19) ◽  
pp. 19250-19258 ◽  
Author(s):  
Ralf Flaig ◽  
Holger Greschik ◽  
Carole Peluso-Iltis ◽  
Dino Moras
Keyword(s):  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Structural Basis ◽  
Specific Activities

scholarly journals Structural Basis for PPARs Activation by the Dual PPARα/γ Agonist Sanguinarine: A Unique Mode of Ligand Recognition

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6012
Author(s):  
Siyu Tian ◽  
Rui Wang ◽  
Shuming Chen ◽  
Jialing He ◽  
Weili Zheng ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Target Genes ◽  
Binding Pocket ◽  
Binding Mode ◽  
Structural Basis ◽  
Peroxisome Proliferator ◽  
Functional Studies ◽  
Glucose And Lipid Metabolism ◽  
Peroxisome Proliferator Activated Receptors ◽  
Dual Agonist

Peroxisome proliferator-activated receptors (PPARs) play crucial roles in glucose and lipid metabolism and inflammation. Sanguinarine is a natural product that is isolated from Sanguinaria Canadensis, a potential therapeutic agent for intervention in chronic diseases. In this study, biochemical and cell-based promoter-reporter gene assays revealed that sanguinarine activated both PPARα and PPARγ, and enhanced their transcriptional activity; thus, sanguinarine was identified as a dual agonist of PPARα/γ. Similar to fenofibrate, sanguinarine upregulates the expression of PPARα-target genes in hepatocytes. Sanguinarine also modulates the expression of key PPARγ-target genes and promotes adipocyte differentiation, but with a lower adipogenic activity compared with rosiglitazone. We report the crystal structure of sanguinarine bound to PPARα, which reveals a unique ligand-binding mode of sanguinarine, dissimilar to the classic Y-shaped binding pocket, which may represent a new pharmacophore that can be optimized for selectively targeting PPARα. Further structural and functional studies uncover the molecular basis for the selectivity of sanguinarine toward PPARα/γ among all three PPARs. In summary, our study identifies a PPARα/γ dual agonist with a unique ligand-binding mode, and provides a promising and viable novel template for the design of dual-targeting PPARs ligands.

Sign in / Sign up

Export Citation Format

Share Document