The role of CXCR3 and its ligands expression in Brucellar spondylitis

Hu, Xin; Shang, Xiaoqian; Wang, Liang; Fan, Jiahui; Wang, Yue; Lv, Jie; Nazierhan, Shaxika; Wang, Hao; Wang, Jing; Ma, Xiumin

doi:10.1186/s12865-020-00390-9

Cited by 2 publications

(2 citation statements)

References 24 publications

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“…CXCR3 is also expressed on a variety of immune cells such as innate lymphocytes, effector T cells, plasmacytoid dendritic cells, subsets of B cells, and within the tumor microenvironment 47,[53][54][55][56] . Aberrant CXCR3 signaling is implicated in glomerulonephritis, and several inflammatory and neuroinflammatory disorders such as chronic pain, bipolar disorder, rheumatoid arthritis, and spondylitis, making it an important therapeutic target [57][58][59][60] . Notably, CXCR3 selectively interacts with only three C-X-C type chemokines i.e.…”

Section: Mainmentioning

confidence: 99%

Molecular basis of ligand promiscuity, structural mimicry, and atypical dimerization in the chemokine receptors

Saha,

Sano,

Sharma

et al. 2024

Preprint

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Selectivity of natural agonists for their cognate receptors is one of the hallmarks of the members of GPCR family, and it is crucial for the specificity of downstream signal-transduction. However, this selectivity often breaks down in the chemokine receptor subfamily, wherein a high degree of promiscuity is observed with one receptor recognizing multiple chemokines and one chemokine binding to multiple receptors. The molecular determinants of such a striking promiscuity for natural ligands in the chemokine-chemokine receptor system remain mostly elusive and represent an important knowledge gap in our current understanding. Here, we carry out a comprehensive transducer-coupling analysis, testing all known C-X-C chemokines on every C-X-C type chemokine receptor, to generate a global fingerprint of the selectivity and promiscuity encoded within this system. Taking lead from our finding, we determined cryo-EM structures of the most promiscuous receptor, CXCR2, in complex with every interacting chemokine, and deciphered the conserved molecular signatures and distinct binding modalities. While most chemokines position themselves on the receptor as a dimer, CXCL6 exhibits a monomeric binding pose induced by a previously unanticipated reorientation of its carboxyl-terminal α-helix, leading to disruption of the dimer interface. Surprisingly, one of the chemokines, CXCL5, induces a ligand-swapped dimer of CXCR2, the first of its kind observed in class A GPCRs, wherein each protomer of the ligand engages its own receptor without any discernible receptor-receptor interface. These unique observations provide a possible structural mechanism for inherent functional specialization encoded in chemokines despite their convergence to a common receptor. Furthermore, we also determined cryo-EM structures of CXCR3 in complex with G-protein-biased and β-arrestin-biased small molecule agonists that elucidate distinct allosteric modulations in the receptor driving their divergent transducer-coupling bias. Guided by structural analysis and experimental validation, we discover that in contrast to previously held notion, small molecule agonists of CXCR3 display robust agonism at CXCR7, an intrinsically biased, β-arrestin-coupled receptor, making them first-in-class dual agonists for chemokine receptors with exclusive βarr-bias at CXCR7. Taken together, our study provides molecular insights into ligand promiscuity and signaling bias at the chemokine receptors, and also demonstrates a proof of principle that naturally encoded structural mimicry can be recapitulated using synthetic pharmacophores with potential implications for developing novel therapeutics.

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Section: Mainmentioning

confidence: 99%

Molecular basis of ligand promiscuity, structural mimicry, and atypical dimerization in the chemokine receptors

Saha,

Sano,

Sharma

et al. 2024

Preprint

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“…Finally, the role of several cytokines, their receptors, and single-nucleotide polymorphisms for cytokine-encoded genes in the inflammatory damaged observed during Brucella spondylitis is still unclear and demands further research [50][51][52].…”

Section: Pathogenesismentioning

confidence: 99%

Brucella Spondylitis: Current Knowledge and Recent Advances

Spernovasilis,

Karantanas,

Markaki

et al. 2024

JCM

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The most prevalent zoonotic disease is brucellosis, which poses a significant threat for worldwide public health. Particularly in endemic areas, spinal involvement is a major source of morbidity and mortality and can complicate the course of the disease. The diagnosis of Brucella spondylitis is challenging and should be suspected in the appropriate epidemiological and clinical context, in correlation with microbiological and radiological findings. Treatment depends largely on the affected parts of the body. Available treatment options include antibiotic administration for an adequate period of time and, when appropriate, surgical intervention. In this article, we examined the most recent data on the pathophysiology, clinical manifestation, diagnosis, and management of spinal brucellosis in adults.

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The role of CXCR3 and its ligands expression in Brucellar spondylitis

Cited by 2 publications

References 24 publications

Molecular basis of ligand promiscuity, structural mimicry, and atypical dimerization in the chemokine receptors

Molecular basis of ligand promiscuity, structural mimicry, and atypical dimerization in the chemokine receptors

Brucella Spondylitis: Current Knowledge and Recent Advances

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