A site of vulnerability at V3 crown defined by HIV-1 bNAb M4008_N1.
A site of vulnerability at V3 crown defined by HIV-1 bNAb M4008_N1.
复制标题
DOI：
10.1038/s41467-021-26846-z
复制
发表时间：
2021-11-09
影响因子：
16.6
通讯作者：
Kong XP
中科院分区：
文献类型：
--
作者：
Chan KW;Luo CC;Lu H;Wu X;Kong XP
鉴定HIV-1包膜（Env）上由广泛中和抗体（bNAb）定义的脆弱位点对于疫苗设计至关重要，我们在这里提出了一个由bNAb M4008_N1定义的脆弱位点，该位点可中和约40%的二级病毒。M4008_N1与BG 505 DS-SOSIP复合物的3.2 μ m分辨率cryo-EM结构显示了一个大而浅的蛋白表位表面，中心位于gp 120的V3冠，并被关键聚糖包围。M4008_N1主要通过其锤头CDR H3与gp 120相互作用，以与V3冠状发夹形成β-折叠相互作用。这使得M4008_N1与融合前Env三聚体的闭合构象相容，因此不同于其他已知的V3冠状mAb。bNAb接近天然Env三聚体中的免疫原性V3冠的这种模式表明了靶向该脆弱位点的免疫原设计策略。广泛中和抗体（bNAb）靶向的HIV Env表面表位的定位对于HIV-1疫苗设计具有极大的意义。在本文中，作者展示了bNAb M4008_N1与BG 505 DS-SOSIP（一种工程化天然样Env三聚体）复合的3.2 kDa cryo-EM结构，并观察到bNAb表位位于V3冠的中心，M4008_N1使用其CDR H3与V3冠的β-发夹形成延伸的β-折叠，其构象稳定在融合前三聚体中。
Identification of vulnerable sites defined by broadly neutralizing antibodies (bNAbs) on HIV-1 envelope (Env) is crucial for vaccine design, and we present here a vulnerable site defined by bNAb M4008_N1, which neutralizes about 40% of a tier-2 virus panel. A 3.2 Å resolution cryo-EM structure of M4008_N1 in complex with BG505 DS-SOSIP reveals a large, shallow protein epitope surface centered at the V3 crown of gp120 and surrounded by key glycans. M4008_N1 interacts with gp120 primarily through its hammerhead CDR H3 to form a β-sheet interaction with the V3 crown hairpin. This makes M4008_N1 compatible with the closed conformation of the prefusion Env trimer, and thus distinct from other known V3 crown mAbs. This mode of bNAb approaching the immunogenic V3 crown in the native Env trimer suggests a strategy for immunogen design targeting this site of vulnerability. Mapping of the HIV Env surface epitopes targeted by broadly neutralizing antibodies (bNAbs) is of great interest for HIV-1 vaccine design. Here, the authors present the 3.2 Å cryo-EM structure of the bNAb M4008_N1 in complex with BG505 DS-SOSIP, an engineered native-like Env trimer and observe that the bNAb epitope is centered at the V3 crown and that M4008_N1 uses its CDR H3 to form an extended β-sheet with the β-hairpin of the V3 crown in a conformation stabilized in the prefusion trimer.
登录
查看更多内容
影响因子：
16.8
作者：
Kong, Leopold;Lee, Jeong Hyun;Doores, Katie J.;Murin, Charles D.;Julien, Jean-Philippe;McBride, Ryan;Liu, Yan;Marozsan, Andre;Cupo, Albert;Klasse, Per-Johan;Hoffenberg, Simon;Caulfield, Michael;King, C. Richter;Hua, Yuanzi;Le, Khoa M.;Khayat, Reza;Deller, Marc C.;Clayton, Thomas;Tien, Henry;Feizi, Ten;Sanders, Rogier W.;Paulson, James C.;Moore, John P.;Stanfield, Robyn L.;Burton, Dennis R.;Ward, Andrew B.;Wilson, Ian A.
通讯作者：
Wilson, Ian A.
影响因子：
64.8
作者：
Huang J;Ofek G;Laub L;Louder MK;Doria-Rose NA;Longo NS;Imamichi H;Bailer RT;Chakrabarti B;Sharma SK;Alam SM;Wang T;Yang Y;Zhang B;Migueles SA;Wyatt R;Haynes BF;Kwong PD;Mascola JR;Connors M
通讯作者：
Connors M
影响因子：
32.4
作者：
Falkowska, Emilia;Le, Khoa M.;Ramos, Alejandra;Doores, Katie J.;Lee, Jeong Hyun;Blattner, Claudia;Ramirez, Alejandro;Derking, Ronald;van Gils, Marit J.;Liang, Chi-Hui;Mcbride, Ryan;von Bredow, Benjamin;Shivatare, Sachin S.;Wu, Chung-Yi;Chan-Hui, Po-Ying;Liu, Yan;Feizi, Ten;Zwick, Michael B.;Koff, Wayne C.;Seaman, Michael S.;Swiderek, Kristine;Moore, John P.;Evans, David;Paulson, James C.;Wong, Chi-Huey;Ward, Andrew B.;Wilson, Ian A.;Sanders, Rogier W.;Poignard, Pascal;Burton, Dennis R.
通讯作者：
Burton, Dennis R.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
6.8
作者：
Agirre, Jon;Davies, Gideon J.;Cowtan, Kevin D.
通讯作者：
Cowtan, Kevin D.