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

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.

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

Science Signaling ◽

10.1126/scisignal.aaw5885 ◽

2020 ◽

Vol 13 (617) ◽

pp. eaaw5885 ◽

Cited By ~ 5

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.

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

PLoS ONE ◽

10.1371/journal.pone.0161894 ◽

2016 ◽

Vol 11 (9) ◽

pp. e0161894 ◽

Cited By ~ 9

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

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

Journal of Experimental Medicine ◽

10.1084/jem.20152023 ◽

2016 ◽

Vol 213 (5) ◽

pp. 791-807 ◽

Cited By ~ 42

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.

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