Structural bases of coronavirus attachment to host aminopeptidase N and its inhibition by neutralizing antibodies.
Structural bases of coronavirus attachment to host aminopeptidase N and its inhibition by neutralizing antibodies.
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DOI：
10.1371/journal.ppat.1002859
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Casasnovas JM
中科院分区：
文献类型：
--
作者：
Reguera J;Santiago C;Mudgal G;Ordoño D;Enjuanes L;Casasnovas JM
冠状病毒 (CoV) 是动物和人类的有包膜病毒，主要与肠道和呼吸道疾病有关，例如严重急性呼吸道综合症和所有普通感冒的 10-20%。冠状病毒的一个子集使用细胞表面氨肽酶 N (APN)（一种膜结合金属蛋白酶）作为细胞进入受体。在这些病毒中，包膜刺突糖蛋白 (S) 介导病毒颗粒与 APN 的附着以及随后的细胞进入，这可以被中和抗体阻断。在这里，我们描述了两种密切相关的冠状病毒株——传染性胃肠炎病毒（TGEV）和猪呼吸道冠状病毒（PRCV）的受体结合域（RBD）的晶体结构，与其受体猪APN（pAPN）或中和抗体复合。这些数据提供了有关二聚体 pAPN 胞外域的结构及其与 CoV S 相互作用的详细信息。我们表明，S 中突出的受体结合边缘决定了 pAPN 胞外域膜远端区域中凹陷的含聚糖表面的病毒结合特异性。 TGEV 和 PRCV 的 RBD 与其他相关 CoV 的 RBD 比较表明，S 受体结合区的构象决定了细胞进入受体的特异性。此外，受体结合边缘是 TGEV 包膜 S 中的主要抗原决定簇，是中和抗体的目标。我们的研究结果提供了关于 CoV 细胞进入和免疫中和的令人信服的观点，并可能有助于抗病毒药物或 CoV 疫苗的设计。 APN 也被认为是癌症治疗的靶点，其结构在此报道，可以促进抗癌药物的开发。细胞表面氨肽酶 N (APN) 是一种用于癌症治疗的膜结合金属蛋白酶靶标，是冠状病毒 (CoV) 的主要细胞进入受体，冠状病毒是导致重要呼吸道和肠道疾病的病原体。在一些 CoV 中，病毒包膜刺突糖蛋白 (S) 介导病毒颗粒与宿主 APN 蛋白的附着和细胞进入，这会被预防 CoV 感染的抗体阻断。此处所示的两种猪 CoV 的 S 蛋白与猪 APN (pAPN) 或中和抗体复合物的晶体结构揭示了某些 CoV 如何与其细胞表面 APN 受体结合，以及抗体如何防止受体结合和感染。该报告揭示了一种独特的病毒受体识别模式，该模式利用与 pAPN 胞外域 N 连接的聚糖，揭示了 CoV 中受体结合特异性的结构决定因素。中和抗体针对用于与 APN 受体结合并进入宿主细胞的病毒残基，这表明有效的 CoV 中和需要针对病毒包膜中关键受体结合基序的免疫反应。这些结构见解与 APN 胞外域的结构一起，提供了与传染病和癌症相关的相关细胞膜过程的令人信服的观点。
The coronaviruses (CoVs) are enveloped viruses of animals and humans associated mostly with enteric and respiratory diseases, such as the severe acute respiratory syndrome and 10–20% of all common colds. A subset of CoVs uses the cell surface aminopeptidase N (APN), a membrane-bound metalloprotease, as a cell entry receptor. In these viruses, the envelope spike glycoprotein (S) mediates the attachment of the virus particles to APN and subsequent cell entry, which can be blocked by neutralizing antibodies. Here we describe the crystal structures of the receptor-binding domains (RBDs) of two closely related CoV strains, transmissible gastroenteritis virus (TGEV) and porcine respiratory CoV (PRCV), in complex with their receptor, porcine APN (pAPN), or with a neutralizing antibody. The data provide detailed information on the architecture of the dimeric pAPN ectodomain and its interaction with the CoV S. We show that a protruding receptor-binding edge in the S determines virus-binding specificity for recessed glycan-containing surfaces in the membrane-distal region of the pAPN ectodomain. Comparison of the RBDs of TGEV and PRCV to those of other related CoVs, suggests that the conformation of the S receptor-binding region determines cell entry receptor specificity. Moreover, the receptor-binding edge is a major antigenic determinant in the TGEV envelope S that is targeted by neutralizing antibodies. Our results provide a compelling view on CoV cell entry and immune neutralization, and may aid the design of antivirals or CoV vaccines. APN is also considered a target for cancer therapy and its structure, reported here, could facilitate the development of anti-cancer drugs. The cell surface aminopeptidase N (APN), a membranebound metalloprotease target for cancer therapy, is a major cell entry receptor for coronaviruses (CoVs), agents that cause important respiratory and enteric diseases. In some CoVs, the virus envelope spike glycoprotein (S) mediates attachment of the virus particles to the host APN protein and cell entry, which is blocked by antibodies that prevent CoV infections. The crystal structures of the S proteins of two porcine CoV in complex with the pig APN (pAPN) or with a neutralizing antibody shown here, reveal how some CoV bind to its cell surface APN receptor and how antibodies prevent receptor binding and infection. The report uncovers a unique virus-receptor recognition mode that engages a glycan N-linked to the pAPN ectodomain, revealing structural determinants of the receptor-binding specificity in CoVs. Neutralizing antibodies target viral residues used for binding to the APN receptor and entry into host cells, showing that efficient CoV neutralization requires immune responses focused toward key receptor binding motifs in the virus envelope. These structural insights, together with the structure of the APN ectodomain, provide a compelling view of relevant cell membrane processes related to infectious diseases and cancer.
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影响因子：
64.8
作者：
Li W;Moore MJ;Vasilieva N;Sui J;Wong SK;Berne MA;Somasundaran M;Sullivan JL;Luzuriaga K;Greenough TC;Choe H;Farzan M
通讯作者：
Farzan M
DOI：
10.1073/pnas.94.13.6798
发表时间：
1997-06-24
影响因子：
11.1
作者：
Martinez, MA;Verdaguer, N;Domingo, E
通讯作者：
Domingo, E
影响因子：
5.6
作者：
Debler, Erik W.;Kaufmann, Gunnar F.;Wilson, Ian A.
通讯作者：
Wilson, Ian A.
DOI：
10.1073/pnas.0606167103
发表时间：
2006-09-05
影响因子：
11.1
作者：
Addlagatta, Anthony;Gay, Leslie;Matthews, Brian W.
通讯作者：
Matthews, Brian W.
DOI：
10.1126/science.1175868
发表时间：
2009-11-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chen L;Kwon YD;Zhou T;Wu X;O'Dell S;Cavacini L;Hessell AJ;Pancera M;Tang M;Xu L;Yang ZY;Zhang MY;Arthos J;Burton DR;Dimitrov DS;Nabel GJ;Posner MR;Sodroski J;Wyatt R;Mascola JR;Kwong PD
通讯作者：
Kwong PD