Cryo-electron microscopic structure of the nucleoprotein-RNA complex of the European filovirus, Lloviu virus

ヨーロッパに分布するエボラウイルス近縁ウイルスの増殖機構を解明 --広範囲の抗フィロウイルス療法の開発に期待--. 京都大学プレスリリース. 2023-04-10.Lloviu virus (LLOV) is a novel filovirus detected in Schreiber’s bats in Europe. The isolation of the infectious LLOV from bats has raised public health concerns. However, the virological and molecular characteristics of LLOV remain largely unknown. The nucleoprotein (NP) of LLOV encapsidates the viral genomic RNA to form a helical NP-RNA complex, which acts as a scaffold for nucleocapsid formation and de novo viral RNA synthesis. In this study, using single-particle cryo-electron microscopy, we determined two structures of the LLOV NP-RNA helical complex, comprising a full-length and a C-terminally truncated NP. The two helical structures were identical, demonstrating that the N-terminal region determines the helical arrangement of the NP. The LLOV NP-RNA protomers displayed a structure similar to that in the Ebola and Marburg virus, but the spatial arrangements in the helix differed. Structure-based mutational analysis identified amino acids involved in the helical assembly and viral RNA synthesis. These structures advance our understanding of the filovirus nucleocapsid formation, and provide a structural basis for the development of anti-filoviral therapeutics

Structural insights into the agonists binding and receptor selectivity of human histamine H₄ receptor

慢性アレルギー疾患に関わるヒスタミン受容体の構造解明 --新規アトピー性皮膚炎・喘息治療薬の開発に貢献--. 京都大学プレスリリース. 2023-10-23.Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H₄ receptor (H₄R) is a potential therapeutic target for chronic inflammatory diseases such as asthma and atopic dermatitis. Here, we show the cryo-electron microscopy structures of the H₄R-Gq complex bound with an endogenous agonist histamine or the selective agonist imetit bound in the orthosteric binding pocket. The structures demonstrate binding mode of histamine agonists and that the subtype-selective agonist binding causes conformational changes in Phe344[7.39], which, in turn, form the “aromatic slot”. The results provide insights into the molecular underpinnings of the agonism of H₄R and subtype selectivity of histamine receptors, and show that the H₄R structures may be valuable in rational drug design of drugs targeting the H₄R

Inhibition of EP4 Signaling Attenuates Aortic Aneurysm Formation

BACKGROUND: Aortic aneurysm is a common but life-threatening disease among the elderly, for which no effective medical therapy is currently available. Activation of prostaglandin E(2) (PGE(2)) is known to increase the expression of matrix metalloproteinase (MMP) and the release of inflammatory cytokines, and may thus exacerbate abdominal aortic aneurysm (AAA) formation. We hypothesized that selective blocking of PGE(2), in particular, EP4 prostanoid receptor signaling, would attenuate the development of AAA. METHODS AND FINDINGS: Immunohistochemical analysis of human AAA tissues demonstrated that EP4 expression was greater in AAA areas than that in non-diseased areas. Interestingly, EP4 expression was proportional to the degree of elastic fiber degradation. In cultured human aortic smooth muscle cells (ASMCs), PGE(2) stimulation increased EP4 protein expression (1.4 ± 0.08-fold), and EP4 stimulation with ONO-AE1-329 increased MMP-2 activity and interleukin-6 (IL-6) production (1.4 ± 0.03- and 1.7 ± 0.14-fold, respectively, P<0.05). Accordingly, we examined the effect of EP4 inhibition in an ApoE(-/-) mouse model of AAA infused with angiotensin II. Oral administration of ONO-AE3-208 (0.01-0.5 mg/kg/day), an EP4 antagonist, for 4 weeks significantly decreased the formation of AAA (45-87% reduction, P<0.05). Similarly, EP4(+/-)/ApoE(-/-) mice exhibited significantly less AAA formation than EP4(+/+)/ApoE(-/-) mice (76% reduction, P<0.01). AAA formation induced by periaortic CaCl(2) application was also reduced in EP4(+/-) mice compared with wild-type mice (73% reduction, P<0.001). Furthermore, in human AAA tissue organ cultures containing SMCs and macrophages, doses of the EP4 antagonist at 10-100 nM decreased MMP-2 activation and IL-6 production (0.6 ± 0.06- and 0.7 ± 0.06-fold, respectively, P<0.05) without increasing MMP-9 activity or MCP-1 secretion. Thus, either pharmacological or genetic EP4 inhibition attenuated AAA formation in multiple mouse and human models by lowering MMP activity and cytokine release. CONCLUSION: An EP4 antagonist that prevents the activation of MMP and thereby inhibits the degradation of aortic elastic fiber may serve as a new strategy for medical treatment of AAA

グリーンランド北西氷床（SIGMA-D）アイスコアを用いた過去157年間の気候復元

第6回極域科学シンポジウム[OM] 極域気水圏11月16日（月）　統計数理研究所 セミナー室2（D304