Kinin Receptor Structures and BDNF-TLR4 Mechanism Reveal Inflammatory Targets
Studies reveal how kinin receptor antagonists achieve subtype selectivity and identify BDNF as a direct TLR4 antagonist, highlighting BDP-12 as a potential therapy for acute inflammatory diseases.
Two studies published in Nature Communications shed light on molecular mechanisms underlying inflammatory disease pathways. One study reports cryo-electron microscopy (cryo-EM) structures of the kinin receptors B1R and B2R bound to antagonists, revealing how subtype selectivity is achieved. The other identifies brain-derived neurotrophic factor (BDNF) as a direct antagonist of Toll-like receptor 4 (TLR4) on macrophages and shows that a synthetic BDNF-derived dodecapeptide preserves anti-inflammatory effects.
In the kinin receptor study, researchers report three cryo-EM structures: B1R in complex with the peptide antagonist R715 and small-molecule antagonist ELN441958, as well as B2R in complex with small-molecule antagonist Win64338. Together with functional assays and molecular docking, these structures unveil the molecular basis of antagonist binding modes in kinin receptors. Three non-conserved residues at the bottom of the ligand binding pocket are identified to confer the antagonist selectivity to B1R and B2R. The results reveal a shared mechanism for antagonism in both receptors, wherein the antagonist binding restricts the conformational changes of the toggle switch tryptophan residue. These insights lay the foundation for the structure-based design of selective antagonists targeting B1R and B2R; such antagonists have shown therapeutic potential in the treatment of angioedema, pancreatitis, and asthma.
The second study investigated BDNF in acute inflammatory lung diseases. Using acute lung injury (ALI) and sepsis models, the researchers demonstrate that BDNF is impaired in pulmonary epithelial cells and negatively correlates with the inflammatory response. Raising the BDNF level alleviates inflammatory lung injury, but these effects are absent in macrophage-deleted mice. Both in vivo and in vitro results show BDNF inhibits macrophage inflammation, and proteomics analysis identifies macrophage TLR4 as a receptor that BDNF antagonizes via direct binding. The BDNF fragment (aa 104-115) is critical for BDNF-TLR4 interaction, and the corresponding synthetic BDNF-derived dodecapeptide (BDP-12) retains TLR4-antagonistic and anti-inflammatory effects both in vitro and in vivo, without pro-proliferative side effects. The findings reveal that epithelial-derived BDNF prevents macrophage inflammation by directly targeting TLR4 and highlight BDP-12 as a potential therapeutic agent for acute inflammatory diseases.