Structural basis of CXC chemokine receptor 2 activation and signalling

Liu, Kaiwen; Wu, Lijie; Yuan, Shuguang; Wu, Meng; Xu, Yueming; Sun, Qianqian; Li, Shu; Zhao, Suwen; Hua, Tian; Liu, Zhijie

doi:10.1038/s41586-020-2492-5

Cited by 145 publications

(181 citation statements)

References 68 publications

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“…CryoEM structure of CXCL8 bound to CXCR2 in the presence of G protein (active form) was recently reported (Liu et al, 2020). The structure reveals that Glu4 is engaged in ionic interactions with three arginines located in ECL2 and ECL3, Leu5 is involved in packing interactions with two valines in the ECL2, and Arg6 forms a H-bond with the carbonyl oxygen of a threonine in ECL3.…”

Section: Discussionmentioning

confidence: 98%

“…11), suggesting these residues finetune Site-II interactions. The cryoEM structures of CXCL8-CXCR2 and CCL20-CCR6 also reveal that the CXCL8 and CCL20 Nterminal are located closer to the surface (Liu et al, 2020;Wasilko et al, 2020). However, crystal structures of 5P7CCL5-CCR5 and vMIPII-CXCR4 complexes reveal that the chemokine N-terminal residues are located deep in the TM groove and are in the proximity of toggle switch residues that trigger the conformational change for receptor activation (Wescott et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Our MD data for the CXCL8-CXCR1 complex indicate that several Site-I interactions are transient, residues that mediate Site-I interactions continue to be dynamic even after Site-II is engaged, and structural plasticity allows the same residue binding at both sites. CryoEM and crystal structures of CXCR2 bound to CXCL8, CCR6 bound to CCL20, CCR5 bound to CCL5 antagonist (5P7-CCL5), CXCR4 bound to vMIPII (a promiscuous viral chemokine antagonist), and a constitutively active viral chemokine receptor US28 bound to CX3CL1 are known (Burg et al, 2015;Liu et al, 2020;Qin et al, 2015;Wasilko et al, 2020;Zheng et al, 2017) (Fig. 7).…”

Section: Discussionmentioning

confidence: 99%

“…The N-domain residues are also not observed in the crystal structures of inhibitor-bound chemokine receptor complexes (Liu et al, 2020;Wu et al, 2010). The structure of CXCL8-CXCR1 complex is not known, but cryoelectron microscopy (cryoEM) and crystal structures of CXCL8 bound to CXCR2 and also of chemokines bound to CXCR4, CCR5, and CCR6 receptors are known (Liu et al, 2020;Qin et al, 2015;Wasilko et al, 2020;Zheng et al, 2017). A significant segment of the receptor Ndomain is also missing in these structures, suggesting Site-I interactions are either weak, lost once the chemokine engages Site-II residues, or that the receptor Site-I residues continue to be dynamic in the chemokine-bound form.…”

mentioning

confidence: 98%

“…Characteristic features of intrinsic disorder include a preponderance of polar and charged residues, lack of a hydrophobic core, engaging in transient but specific interactions, and becoming structured on binding a protein partner (Latysheva et al, 2015;Uversky, 2019;van der Lee et al, 2014;Wright and Dyson, 2015). The N-domain residues are also not observed in the crystal structures of inhibitor-bound chemokine receptor complexes (Liu et al, 2020;Wu et al, 2010). The structure of CXCL8-CXCR1 complex is not known, but cryoelectron microscopy (cryoEM) and crystal structures of CXCL8 bound to CXCR2 and also of chemokines bound to CXCR4, CCR5, and CCR6 receptors are known (Liu et al, 2020;Qin et al, 2015;Wasilko et al, 2020;Zheng et al, 2017).…”

mentioning

confidence: 99%

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Long-range coupled motions underlie ligand recognition by a chemokine receptor

Sepuru¹,

Nair

Prakash

et al. 2020

Preprint

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Chemokines are unusual class-A GPCR agonists because of their large size (~10 kDa) and binding at two distinct receptor sites: N-terminal domain (Site-I, unique to chemokines) and a groove defined by extracellular loop/transmembrane helices (Site-II, shared with all small molecule class-A ligands). Whereas binding at Site-II triggers receptor activation, the role of Site-I is not known. Structures and sequence analysis reveal that the receptor N-terminal domains (N-domains) are flexible and contain intrinsic disorder. Using a hybrid NMR-MD approach, we characterized the role of Site-I interactions for the CXCL8-CXCR1 pair. NMR data indicate that the CXCR1 N-domain becomes structured on binding and that the binding interface is extensive with 30% of CXCL8 residues participating in this initial interaction. MD simulations indicate that CXCL8 bound at Site-I undergoes extensive reorganization on engaging Site-II with several residues initially engaged at Site-I also engaging Site-II. We conclude that structural plasticity of Site-I interactions plays an active role in driving ligand recognition by a chemokine receptor.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 99%

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Long-range coupled motions underlie ligand recognition by a chemokine receptor

Sepuru¹,

Nair

Prakash

et al. 2020

Preprint

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A Cholesterol Dimer Stabilizes the Inactivated State of an Inward‐Rectifier Potassium Channel

et al. 2022

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Cholesterol oligomers reside in multiple membrane protein X‐ray crystal structures. Yet, there is no direct link between these oligomers and a biological function. Here we present the structural and functional details of a cholesterol dimer that stabilizes the inactivated state of an inward‐rectifier potassium channel KirBac1.1. K+ efflux assays confirm that high cholesterol concentration reduces K+ conductance. We then determine the structure of the cholesterol‐KirBac1.1 complex using Xplor‐NIH simulated annealing calculations driven by solid‐state NMR distance measurements. These calculations identified an α–α cholesterol dimer docked to a cleft formed by adjacent subunits of the homotetrameric protein. We compare these results to coarse grain molecular dynamics simulations. This is one of the first examples of a cholesterol oligomer performing a distinct biological function and structural characterization of a conserved promiscuous lipid binding region.

show abstract

A Cholesterol Dimer Stabilizes the Inactivated State of an Inward‐Rectifier Potassium Channel

et al. 2022

View full text Add to dashboard Cite

Cholesterol oligomers reside in multiple membrane protein X-ray crystal structures. Yet, there is no direct link between these oligomers and a biological function. Here we present the structural and functional details of a cholesterol dimer that stabilizes the inactivated state of an inward-rectifier potassium channel KirBac1.1. K + efflux assays confirm that high cholesterol concentration reduces K + conductance. We then determine the structure of the cholesterol-Kir-Bac1.1 complex using Xplor-NIH simulated annealing calculations driven by solid-state NMR distance measurements. These calculations identified an α-α cholesterol dimer docked to a cleft formed by adjacent subunits of the homotetrameric protein. We compare these results to coarse grain molecular dynamics simulations. This is one of the first examples of a cholesterol oligomer performing a distinct biological function and structural characterization of a conserved promiscuous lipid binding region.

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Structural basis of CXC chemokine receptor 2 activation and signalling

Cited by 145 publications

References 68 publications

Long-range coupled motions underlie ligand recognition by a chemokine receptor

Long-range coupled motions underlie ligand recognition by a chemokine receptor

A Cholesterol Dimer Stabilizes the Inactivated State of an Inward‐Rectifier Potassium Channel

A Cholesterol Dimer Stabilizes the Inactivated State of an Inward‐Rectifier Potassium Channel

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