Nipah and Hendra Viruses Use an Adjustable Latch in Receptor Engagement.

IF 3.8 2区医学 Q2 CHEMISTRY, MEDICINAL

ACS Infectious Diseases Pub Date : 2025-09-26 DOI:10.1021/acsinfecdis.4c01040

Mitchell S von Itzstein, Moritz Winger, Alpeshkumar K Malde, Stephanie Holt, Sarah McAtamney, Lauren Hartley-Tassell, Thomas Ve, Andrea Maggioni, Mark von Itzstein

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Abstract

Nipah (NiV) and Hendra viruses (HeV) have emerged as deadly zoonotic pathogens over the last three decades. Like all paramyxoviruses, Henipaviruses utilize a surface glycoprotein to attach to and invade targeted cells. Inhibiting this attachment glycoprotein is a promising strategy for developing effective antihenipaviral drugs. A multidisciplinary approach has been employed to investigate the structures of HeV and NiV attachment glycoproteins, identifying a flexible region near their binding site. This region, loop 240, can adopt an open conformation in unliganded attachment glycoproteins and a closed "latch" conformation in the presence of their cognate receptor Ephrin B2. Site-directed mutagenesis of the HeV attachment glycoproteins has shown that the engagement of R242 with Ephrin B2 plays an important role in the binding mechanism. This discovery provides greater insight into the dynamic nature of henipaviral attachment proteins and has implications for antiviral drug development.

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尼帕病毒和亨德拉病毒在受体结合中使用可调节的锁存器。

尼帕病毒（NiV）和亨德拉病毒（HeV）在过去三十年中已成为致命的人畜共患病原体。像所有副黏液病毒一样，亨尼帕病毒利用表面糖蛋白附着并侵入目标细胞。抑制这种附着糖蛋白是开发有效的抗亨尼帕病毒药物的一个有前途的策略。采用多学科方法研究了HeV和NiV附着糖蛋白的结构，确定了它们结合位点附近的一个柔性区域。该区域，环240，在无配体附着糖蛋白中可以采用开放构象，在其同源受体Ephrin B2存在时可以采用封闭的“闩锁”构象。对HeV糖蛋白的定点诱变研究表明，R242与Ephrin B2的结合在其结合机制中起重要作用。这一发现对亨尼帕病毒附着蛋白的动态特性提供了更深入的了解，并对抗病毒药物的开发具有重要意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

期刊介绍： ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.