Structural basis for highly effective HIV-1 neutralization by CD4-mimetic miniproteins revealed by 1.5 Å cocrystal structure of gp120 and M48U1.
Structural basis for highly effective HIV-1 neutralization by CD4-mimetic miniproteins revealed by 1.5 Å cocrystal structure of gp120 and M48U1.
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DOI：
10.1016/j.str.2013.04.015
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发表时间：
2013-06-04
期刊：
影响因子：
5.7
通讯作者：
Kwong, Peter D.
中科院分区：
文献类型：
--
作者：
Acharya, Priyamvada;Luongo, Timothy S.;Louder, Mark K.;McKee, Krisha;Yang, Yongping;Kwon, Young Do;Mascola, John R.;Kessler, Pascal;Martin, Loic;Kwong, Peter D.
HIV-1 gp 120包膜糖蛋白和CD 4受体之间的界面含有一个不寻常的界面空腔，即“Phe 43空腔”，具有非天然延伸的CD 4的微蛋白模拟物可以潜在地利用该空腔来增强它们对HIV-1的中和作用。在这里，我们报告共晶体结构的HIV-1 gp 120与微蛋白M48 U1和M48 U 7，插入环己基甲氧基和5-羟基戊基甲氧基扩展，分别到Phe 43腔。两种插入物都显示出柔性和疏水相互作用，但M48 U1插入物比M48 U 7插入物显示出与Phe 43腔更好的形状互补性。gp 120构象的细微变化在优化拟合中发挥了重要作用。使用M48 U1，这些转化为0.015 nM的YU 2-gp 120亲和力，并且中和了所有180种测试的循环HIV-1菌株，除了具有非典型Phe 43腔的进化枝A/E分离株。配体化学、形状互补、表面掩埋和gp 120构象协同作用以调节配体与gp 120-Phe 43腔的结合，并且当优化时，可以实现HIV-1的近泛中和。
The interface between HIV-1 gp120 envelope glycoprotein and CD4 receptor contains an unusual interfacial cavity, the “Phe43 cavity”, which miniprotein mimetics of CD4 with non-natural extensions can potentially utilize to enhance their neutralization of HIV-1. Here we report co-crystal structures of HIV-1 gp120 with miniproteins M48U1 and M48U7, which insert cyclohexylmethoxy and 5-hydroxypentylmethoxy extensions, respectively, into the Phe43 cavity. Both inserts displayed flexibility and hydrophobic interactions, but the M48U1 insert showed better shape complementarity with the Phe43 cavity than the M48U7 insert. Subtle alteration in gp120 conformation played a substantial role in optimizing fit. With M48U1, these translated into a YU2-gp120 affinity of 0.015 nM and neutralization of all 180-circulating HIV-1 strains tested, except clade-A/E isolates with non-canonical Phe43 cavities. Ligand chemistry, shape complementary, surface burial, and gp120 conformation act in concert to modulate binding of ligands to the gp120-Phe43 cavity and, when optimized, can effect near pan-neutralization of HIV-1.
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影响因子：
3.3
作者：
Lagenaur LA;Villarroel VA;Bundoc V;Dey B;Berger EA
通讯作者：
Berger EA
影响因子：
3.5
作者：
LaLonde, Judith M.;Elban, Mark A.;Courter, Joel R.;Sugawara, Akihiro;Soeta, Takahiro;Madani, Navid;Princiotto, Amy M.;Do Kwon, Young;Kwong, Peter D.;Schoen, Arne;Freire, Ernesto;Sodroski, Joseph;Smith, Amos B., III
通讯作者：
Smith, Amos B., III
影响因子：
4.8
作者：
Arthos, J;Cicala, C;Fauci, AS
通讯作者：
Fauci, AS
影响因子：
3.3
作者：
Grupping, Katrijn;Selhorst, Philippe;Arien, Kevin K.
通讯作者：
Arien, Kevin K.
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