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 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.

scholarly journals Computational Analysis of the Ligand Binding Site of the Extracellular ATP Receptor, DORN1

PLoS ONE ◽  
2016 ◽  
Vol 11 (9) ◽  
pp. e0161894 ◽  
Author(s):  
Cuong The Nguyen ◽  
Kiwamu Tanaka ◽  
Yangrong Cao ◽  
Sung-Hwan Cho ◽  
Dong Xu ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Computational Analysis ◽  
Extracellular Atp ◽  
Ligand Binding Site

scholarly journals Killer cell immunoglobulin-like receptor 3DL1 polymorphism defines distinct hierarchies of HLA class I recognition

2016 ◽  
Vol 213 (5) ◽  
pp. 791-807 ◽  
Author(s):  
Philippa M. Saunders ◽  
Phillip Pymm ◽  
Gabriella Pietra ◽  
Victoria A. Hughes ◽  
Corinne Hitchen ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Natural Killer ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Ligand Binding Site ◽  
Functional Studies ◽  
Generic Framework ◽  
The Impact

Natural killer (NK) cells play a key role in immunity, but how HLA class I (HLA-I) and killer cell immunoglobulin-like receptor 3DL1 (KIR3DL1) polymorphism impacts disease outcome remains unclear. KIR3DL1 (*001/*005/*015) tetramers were screened for reactivity against a panel of HLA-I molecules. This revealed different and distinct hierarchies of specificity for each KIR3DL1 allotype, with KIR3DL1*005 recognizing the widest array of HLA-I ligands. These differences were further reflected in functional studies using NK clones expressing these specific KIR3DL1 allotypes. Unexpectedly, the Ile/Thr80 dimorphism in the Bw4-motif did not categorically define strong/weak KIR3DL1 recognition. Although the KIR3DL1*001, *005, and *015 polymorphisms are remote from the KIR3DL1–HLA-I interface, the structures of these three KIR3DL1–HLA-I complexes showed that the broader HLA-I specificity of KIR3DL1*005 correlated with an altered KIR3DL1*005 interdomain positioning and increased mobility within its ligand-binding site. Collectively, we provide a generic framework for understanding the impact of KIR3DL1 polymorphism on the recognition of HLA-I allomorphs.

Constraints of Opsin Structure on the Ligand-binding Site: Studies with Ring-fused Retinals¶

2002 ◽  
Vol 76 (6) ◽  
pp. 606 ◽  
Author(s):  
Takahiro Hirano ◽  
In Taek Lim ◽  
Don Moon Kim ◽  
Xiang-Guo Zheng ◽  
Kazuo Yoshihara ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Ligand Binding Site
Sign in / Sign up

Export Citation Format

Share Document