Chemokine Receptor Crystal Structures: What Can Be Learned from Them?

Arimont, Marta; Hoffmann, Carsten; Graaf, Chris de; Leurs, Rob

doi:10.1124/mol.119.117168

Cited by 29 publications

(27 citation statements)

References 119 publications

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“…To date, 19 canonical chemokine receptors, including CC, CXC, CX3C and XC subfamilies, and four atypical chemokine receptors (ACKRs) have been characterised in humans [ 17 , 19 ]. The structure of chemokine receptors is highly conserved in the presence of a DRYLAIV motif within the second ICL, except for the ACKRs [ 19 , 20 ].…”

Section: Background On the Chemokine Signalling Systemmentioning

confidence: 99%

Latest update on chemokine receptors as therapeutic targets

Lai

Müeller

2021

Biochemical Society Transactions

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The chemokine system plays a fundamental role in a diverse range of physiological processes, such as homeostasis and immune responses. Dysregulation in the chemokine system has been linked to inflammatory diseases and cancer, which renders chemokine receptors to be considered as therapeutic targets. In the past two decades, around 45 drugs targeting chemokine receptors have been developed, yet only three are clinically approved. The challenging factors include the limited understanding of aberrant chemokine signalling in malignant diseases, high redundancy of the chemokine system, differences between cell types and non-specific binding of the chemokine receptor antagonists due to the broad ligand-binding pockets. In recent years, emerging studies attempt to characterise the chemokine ligand–receptor interactions and the downstream signalling protein–protein interactions, aiming to fine tuning to the promiscuous interplay of the chemokine system for the development of precision medicine. This review will outline the updates on the mechanistic insights in the chemokine system and propose some potential strategies in the future development of targeted therapy.

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Section: Background On the Chemokine Signalling Systemmentioning

confidence: 99%

Latest update on chemokine receptors as therapeutic targets

Lai

Müeller

2021

Biochemical Society Transactions

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“…Another important subfamily of class A GPCRs with a number of key physiologic roles are the Chemokine receptors [17]. So far (till 2020) only 5 different chemokine receptor complexes have had their crystal structure solved by researchers and they are CXCR4 [18] (PDB IDs: 3ODU, 3OE0, 3OE6, 3OE8, 3OE9, and 4RWS [18,19]), CCR5 [20] (PDB IDs: 4MBS, 5UIW, 6AKX, and 6AKY [21][22][23]), US28 [24] (PDB IDs: 4XT1, 4XT3, 5WB1, and 5WB2 [24,25]), CCR2 [26] (PDB IDs: 5T1A, 6GPS, and 6GPX [26,27]) and CCR9 [28] (PDB ID: 5LWE [28]).…”

Section: A Brief History On the Structural Study Of Gpcrsmentioning

confidence: 99%

Importance of Homology Modeling for Predicting the Structures of GPCRs

Sailapathi¹,

Gunalan²,

Somarathinam³

et al. 2021

Homology Molecular Modeling - Perspectives and Applications

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Homology modeling is one of the key discoveries that led to a rapid paradigm shift in the field of computational biology. Homology modeling obtains the three dimensional structure of a target protein based on the similarity between template and target sequences and this technique proves to be efficient when it comes to studying membrane proteins that are hard to crystallize like GPCR as it provides a higher degree of understanding of receptor-ligand interaction. We get profound insights on structurally unsolved, yet clinically important drug targeting proteins through single or multiple template modeling. The advantages of homology modeling studies are often used to overcome various problems in crystallizing GPCR proteins that are involved in major disease-related pathways, thus paving way to more structural insights via in silico models when there is a lack of experimentally solved structures. Owing to their pharmaceutical significance, structural analysis of various GPCR proteins using techniques like homology modeling is of utmost importance.

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“…More recently, crystal structures have resolved site-II interactions, but only a partial site-I engagement [ 29 , 30 ]. However, a superposition of structures with respect to the bound chemokine indicates that the placement of the receptor N-terminus could be receptor-specific [ 31 ]. Although the two-site model served as the initial framework of functionally relevant interactions leading to chemokine-receptor binding, growing literature suggests a need for more complex models accounting for the dynamic mechanism of receptor-ligand binding [ 32 ].…”

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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Chemokine Receptor Crystal Structures: What Can Be Learned from Them?

Cited by 29 publications

References 119 publications

Latest update on chemokine receptors as therapeutic targets

Latest update on chemokine receptors as therapeutic targets

Importance of Homology Modeling for Predicting the Structures of GPCRs

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

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