The Inside Story: Crystal Structure of the Chemokine Receptor CCR7 with an Intracellular Allosteric Antagonist

Saha, Shirsha; Shukla, Arun K.

doi:10.1021/acs.biochem.9b00893

Cited by 8 publications

(8 citation statements)

References 5 publications

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“…Interestingly, both molecules dock in the intracellular part of the receptor cavity. CCR7 is closest in homology to CCR2 and CCR9, both of which are also reported with allosteric antagonist bound in the intracellular part of the receptor cavity, strongly suggesting that this is a binding pocket for this group of chemokine receptors [285].…”

Section: Small Molecule Antagonism Of Ccr7mentioning

confidence: 63%

CCR7 as a therapeutic target in Cancer

Salem

Alotaibi

Mroueh

et al. 2021

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Section: Small Molecule Antagonism Of Ccr7mentioning

confidence: 63%

CCR7 as a therapeutic target in Cancer

Salem

Alotaibi

Mroueh

et al. 2021

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…At the moment no drugs targeting CCR7 are on the market; however, recently, antagonists of CCR7 were disclosed in the literature. Both Navarixin and Cmp1220 inhibit signaling via CCR7 by stabilizing the receptor in an inactive state through interactions with the receptor from the intracellular side [ 166 , 200 ]. Whether the CCR7 antagonists can be used in disease control without adverse effects is unknown as CCR7 is important for upholding homeostatic immune functions [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cells and CCR7 Expression: An Important Factor for Autoimmune Diseases, Chronic Inflammation, and Cancer

Brandum

Jørgensen

Hjortø

2021

IJMS

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Chemotactic cytokines—chemokines—control immune cell migration in the process of initiation and resolution of inflammatory conditions as part of the body’s defense system. Many chemokines also participate in pathological processes leading up to and exacerbating the inflammatory state characterizing chronic inflammatory diseases. In this review, we discuss the role of dendritic cells (DCs) and the central chemokine receptor CCR7 in the initiation and sustainment of selected chronic inflammatory diseases: multiple sclerosis (MS), rheumatoid arthritis (RA), and psoriasis. We revisit the binary role that CCR7 plays in combatting and progressing cancer, and we discuss how CCR7 and DCs can be harnessed for the treatment of cancer. To provide the necessary background, we review the differential roles of the natural ligands of CCR7, CCL19, and CCL21 and how they direct the mobilization of activated DCs to lymphoid organs and control the formation of associated lymphoid tissues (ALTs). We provide an overview of DC subsets and, briefly, elaborate on the different T-cell effector types generated upon DC–T cell priming. In the conclusion, we promote CCR7 as a possible target of future drugs with an antagonistic effect to reduce inflammation in chronic inflammatory diseases and an agonistic effect for boosting the reactivation of the immune system against cancer in cell-based and/or immune checkpoint inhibitor (ICI)-based anti-cancer therapy.

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“…Structural studies of CCR7 are conducive to the discovery of possible binding sites and further specific antagonists or agonists of it. This way, navarixin (SCH-527123 or MK-7123) and Cmp2105 were found to stabilize CCR7 in an inactive state through interactions with its intracellular side (Jaeger et al, 2019;Saha and Shukla, 2020). In addition, navarixin is undergoing several clinical trials currently, including psoriasis, allergen-induced asthma, and chronic obstructive pulmonary disease, indicating its potential to benefit DC-related clinical immunotherapy (Salem et al, 2021).…”

Section: Immunotherapy Targeting Ccr7 Directlymentioning

confidence: 99%

New Insights of CCR7 Signaling in Dendritic Cell Migration and Inflammatory Diseases

Hong

Yang

et al. 2022

Front. Pharmacol.

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CCR7, collaborated with its ligands CCL19 and CCL21, controls extensive migratory events in the immune system. CCR7-bearing dendritic cells can swarm into T-cell zones in lymph nodes, initiating the antigen presentation and T-cell response. Abnormal expression of CCR7 in dendritic cells will cause a series of inflammatory diseases due to the chaotic dendritic cell trafficking. In this review, we take an in-depth look at the structural–functional domains of CCR7 and CCR7-bearing dendritic cell trajectory to lymph nodes. Then, we summarize the regulatory network of CCR7, including transcriptional regulation, translational and posttranslational regulation, internalization, desensitization, and recycling. Furthermore, the potential strategies of targeting the CCR7 network to regulate dendritic cell migration and to deal with inflammatory diseases are integrated, which not only emphasizes the possibility of CCR7 to be a potential target of immunotherapy but also has an implication on the homing of dendritic cells to benefit inflammatory diseases.

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The Inside Story: Crystal Structure of the Chemokine Receptor CCR7 with an Intracellular Allosteric Antagonist

Cited by 8 publications

References 5 publications

CCR7 as a therapeutic target in Cancer

CCR7 as a therapeutic target in Cancer

Dendritic Cells and CCR7 Expression: An Important Factor for Autoimmune Diseases, Chronic Inflammation, and Cancer

New Insights of CCR7 Signaling in Dendritic Cell Migration and Inflammatory Diseases

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