Membrane-induced organization and dynamics of the N-terminal domain of chemokine receptor CXCR1: insights from atomistic simulations

Kharche, Shalmali; Joshi, M. P.; Sengupta, Durba; Chattopadhyay, Amitabha

doi:10.1016/j.chemphyslip.2017.09.003

Cited by 10 publications

(5 citation statements)

References 53 publications

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“…The interactions of IL8 were assessed using NMR with CXCR1 constructs of varying length, clearly indicating that IL8 could not bind to CXCR1 when the receptor N-terminal was truncated [ 37 ]. In addition, IL8 was shown to bind with higher affinity to the CXCR1 N-terminal region in a lipid environment relative to that in solution [ 36 ], in agreement with our previous work using fluorescence and molecular dynamics (MD) simulations which show membrane interaction of the CXCR1 N-terminal region [ 38 – 40 ].…”

Section: Introductionsupporting

confidence: 87%

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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Section: Introductionsupporting

confidence: 87%

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

et al. 2021

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“…79 Interactions with membrane lipids have been shown to result in differences in the overall conformational dynamics of transmembrane domains and loop regions of GPCRs. 42,52,80 Several atomistic force-fields, including CHARMM, 41,52 OPLS, 42 and Desmond force-fields, 78 have been used for these studies. Detailed comparisons between these force-fields have not been reported, although most cholesterol sites that have been identified appear to be force-field-independent.…”

Section: ■ Distinguishing Between Atomistic and Coarse-grain Simulationsmentioning

confidence: 99%

“…In particular, they have been able to identify important interactions of GPCRs with lipids, , and a few have been successful in mapping out multiple cholesterol interaction sites. ,,, Interestingly, a competition between cholesterol and the ligand at the orthosteric ligand binding site has been reported . Interactions with membrane lipids have been shown to result in differences in the overall conformational dynamics of transmembrane domains and loop regions of GPCRs. ,, Several atomistic force-fields, including CHARMM, , OPLS, and Desmond force-fields, have been used for these studies. Detailed comparisons between these force-fields have not been reported, although most cholesterol sites that have been identified appear to be force-field-independent.…”

Section: Distinguishing Between Atomistic and Coarse-grain Simulationsmentioning

confidence: 99%

Exploring GPCR–Lipid Interactions by Molecular Dynamics Simulations: Excitements, Challenges, and the Way Forward

et al. 2018

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Gprotein-coupled receptors (GPCRs) are seven transmembrane receptors that mediate a large number of cellular responses and are important drug targets. One of the current challenges in GPCR biology is to analyze the molecular signatures of receptor-lipid interactions and their subsequent effects on GPCR structure, organization, and function. Molecular dynamics simulation studies have been successful in predicting molecular determinants of receptor-lipid interactions. In particular, predicted cholesterol interaction sites appear to correspond well with experimentally determined binding sites and estimated time scales of association. In spite of several success stories, the methodologies in molecular dynamics simulations are still emerging. In this Feature Article, we provide a comprehensive overview of coarse-grain and atomistic molecular dynamics simulations of GPCR-lipid interaction in the context of experimental observations. In addition, we discuss the effect of secondary and tertiary structural constraints in coarse-grain simulations in the context of functional dynamics and structural plasticity of GPCRs. We envision that this comprehensive overview will help resolve differences in computational studies and provide a way forward.

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“…Experimental models suggest that electrostatic interactions between the N-terminal parts of the CXCR1 receptor and the lipid parts of the cell membrane are important for the three-dimensional folding of the receptor chain [ 148 , 149 , 150 , 151 ]. These interactions increase the affinity of CXCR1 for CXCL8 [ 148 ]. Furthermore, after CXCR1 ligation by CXCL8, the receptor relocalizes to lipid rafts that facilitate its G-protein-mediated signaling [ 152 ].…”

Section: Structural Lipids and Neutrophil Migration: The Membrane Str...mentioning

confidence: 99%

“…Targeting of lipid mediators. Targeting of lipids is suggested both by the importance of neutrophil membrane stiffness/lipid profile, neutrophil polarization, lipid rafts, and caveola as well as chemotactic lipid mediators in the regulation of neutrophil migration, and lipids are also important for the endothelial cell stiffness that influence neutrophil transmigration ( Section 2.3 and Section 7 ; [ 25 , 26 , 27 , 46 , 47 , 88 , 89 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 148 , 149 , 150 , 151 , 152 , 153 ]). Statins were tried in the treatment of sepsis, especially in patients with septic pulmonary infections [ 369 , 432 , 433 ].…”

Section: Therapeutic Targeting Of Neutrophils In Sepsis: Tried and Su...mentioning

confidence: 99%

The Regulation of Neutrophil Migration in Patients with Sepsis: The Complexity of the Molecular Mechanisms and Their Modulation in Sepsis and the Heterogeneity of Sepsis Patients

Bruserud

Mosevoll

Bruserud

et al. 2023

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Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Common causes include gram-negative and gram-positive bacteria as well as fungi. Neutrophils are among the first cells to arrive at an infection site where they function as important effector cells of the innate immune system and as regulators of the host immune response. The regulation of neutrophil migration is therefore important both for the infection-directed host response and for the development of organ dysfunctions in sepsis. Downregulation of CXCR4/CXCL12 stimulates neutrophil migration from the bone marrow. This is followed by transmigration/extravasation across the endothelial cell barrier at the infection site; this process is directed by adhesion molecules and various chemotactic gradients created by chemotactic cytokines, lipid mediators, bacterial peptides, and peptides from damaged cells. These mechanisms of neutrophil migration are modulated by sepsis, leading to reduced neutrophil migration and even reversed migration that contributes to distant organ failure. The sepsis-induced modulation seems to differ between neutrophil subsets. Furthermore, sepsis patients should be regarded as heterogeneous because neutrophil migration will possibly be further modulated by the infecting microorganisms, antimicrobial treatment, patient age/frailty/sex, other diseases (e.g., hematological malignancies and stem cell transplantation), and the metabolic status. The present review describes molecular mechanisms involved in the regulation of neutrophil migration; how these mechanisms are altered during sepsis; and how bacteria/fungi, antimicrobial treatment, and aging/frailty/comorbidity influence the regulation of neutrophil migration.

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Membrane-induced organization and dynamics of the N-terminal domain of chemokine receptor CXCR1: insights from atomistic simulations

Cited by 10 publications

References 53 publications

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

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

Exploring GPCR–Lipid Interactions by Molecular Dynamics Simulations: Excitements, Challenges, and the Way Forward

The Regulation of Neutrophil Migration in Patients with Sepsis: The Complexity of the Molecular Mechanisms and Their Modulation in Sepsis and the Heterogeneity of Sepsis Patients

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