Extramembranous Regions in G Protein-Coupled Receptors: Cinderella in Receptor Biology?

Pal, Sreetama; Chattopadhyay, Amitabha

doi:10.1007/s00232-019-00092-3

Cited by 25 publications

(15 citation statements)

References 168 publications

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“…Many GPCRs have extended flexible N-termini, which are often posttranslationally modified and contribute to ligand binding and receptor signaling [55]. For chemokine receptors, the Nterminus is known to be a determinant of chemokine affinity and to contribute to specificity [14,17]; it is also increasingly being appreciated for its role in signaling efficacy [18,22,23].…”

Section: Discussionmentioning

confidence: 99%

Crosslinking-guided geometry of a complete CXC receptor-chemokine complex and the basis of chemokine subfamily selectivity

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Crosslinking-guided geometry of a complete CXC receptor-chemokine complex and the basis of chemokine subfamily selectivity

et al. 2020

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“…Many GPCRs have extended flexible N-termini, which are often post-translationally modified and contribute to ligand binding and receptor signaling [55]. For chemokine receptors, the N-terminus is known to be a determinant of chemokine affinity and to contribute to specificity [14,17]}; it is also increasingly being appreciated for its role in signaling efficacy [18,22,23].…”

Section: Discussionmentioning

confidence: 99%

Crosslinking-guided geometry of a complete CXC receptor-chemokine complex and the basis of chemokine subfamily selectivity

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Stephens

Gustavsson

et al. 2020

Preprint

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AbstractChemokines and their receptors are orchestrators of cell migration in humans. Because dysregulation of the receptor-chemokine system leads to inflammation and cancer, both chemokines and receptors are highly sought therapeutic targets. Yet one of the barriers for their therapeutic targeting is the limited understanding of the structural principles behind receptor-chemokine recognition and selectivity. The existing structures do not include CXC subfamily complexes and lack information about the receptor distal N-termini, despite the importance of the latter in signaling, regulation, and bias. Here we report the discovery of the geometry of the complex between full-length CXCR4, a prototypical CXC receptor and driver of cancer metastasis, and its endogenous ligand CXCL12. By comprehensive disulfide crosslinking, we establish the existence and the structure of a novel interface between the CXCR4 distal N-terminus and CXCL12 β1-strand, while also recapitulating earlier findings from NMR, modeling and crystallography of homologous receptors. A crosslinking-informed high-resolution model of the CXCR4-CXCL12 complex pinpoints the interaction determinants and reveals the occupancy of the receptor major subpocket by the CXCL12 proximal N-terminus. This newly found positioning of the chemokine proximal N-terminus provides a structural explanation of CXC receptor-chemokine selectivity against other subfamilies. Our findings challenge the traditional two-site understanding of receptor-chemokine recognition, suggest the possibility of new affinity and signaling determinants, and fill a critical void on the structural map of an important class of therapeutic targets. These results will aid the rational design of selective chemokine-receptor-targeting small molecules and biologics with novel pharmacology.

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“…Recent advances in GPCR structural biology have helped to resolve the structure of transmembrane domains of several GPCRs. However, the interconnecting loops and the N- and C-terminal extramembranous regions remain largely unresolved [ 5 , 6 ]. The high flexibility of these loop regions makes it challenging to resolve their conformational states, but at the same time gives them a functional significance [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Both direct interaction ( e . g ., between intracellular loop 3 (ICL3) and effectors [ 8 ]) and allosteric modulation by extramembranous loops (such as extracellular loops 2 and 3 (ECL2, ECL3) [ 6 , 9 , 10 ]) have been reported in various GPCRs. The N-terminal region, known to interact with ligands [ 11 ] in GPCRs such as chemokine receptors [ 12 – 14 ], is of special interest in this context.…”

Section: Introductionmentioning

confidence: 99%

Conformational plasticity and dynamic interactions of the N-terminal domain of the chemokine receptor CXCR1

et al. 2021

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The dynamic interactions between G protein-coupled receptors (GPCRs) and their cognate protein partners are central to several cell signaling pathways. For example, the association of CXC chemokine receptor 1 (CXCR1) with its cognate chemokine, interleukin-8 (IL8 or CXCL8) initiates pathways leading to neutrophil-mediated immune responses. The N-terminal domain of chemokine receptors confers ligand selectivity, but unfortunately the conformational dynamics of this intrinsically disordered region remains unresolved. In this work, we have explored the interaction of CXCR1 with IL8 by microsecond time scale coarse-grain simulations, complemented by atomistic models and NMR chemical shift predictions. We show that the conformational plasticity of the apo-receptor N-terminal domain is restricted upon ligand binding, driving it to an open C-shaped conformation. Importantly, we corroborated the dynamic complex sampled in our simulations against chemical shift perturbations reported by previous NMR studies and show that the trends are similar. Our results indicate that chemical shift perturbation is often not a reporter of residue contacts in such dynamic associations. We believe our results represent a step forward in devising a strategy to understand intrinsically disordered regions in GPCRs and how they acquire functionally important conformational ensembles in dynamic protein-protein interfaces.

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Extramembranous Regions in G Protein-Coupled Receptors: Cinderella in Receptor Biology?

Cited by 25 publications

References 168 publications

Crosslinking-guided geometry of a complete CXC receptor-chemokine complex and the basis of chemokine subfamily selectivity

Crosslinking-guided geometry of a complete CXC receptor-chemokine complex and the basis of chemokine subfamily selectivity

Crosslinking-guided geometry of a complete CXC receptor-chemokine complex and the basis of chemokine subfamily selectivity

Conformational plasticity and dynamic interactions of the N-terminal domain of the chemokine receptor CXCR1

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