Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env

被引：297

作者：

Do Kwon, Young ^{[1
]}

Pancera, Marie ^{[1
]}

Acharya, Priyamvada ^{[1
]}

Georgiev, Ivelin S. ^{[1
]}

Crooks, Emma T. ^{[2
]}

Gorman, Jason ^{[1
]}

Joyce, M. Gordon ^{[1
]}

Guttman, Miklos ^{[3
]}

Ma, Xiaochu ^{[4
]}

Narpala, Sandeep ^{[1
]}

Soto, Cinque ^{[1
]}

Terry, Daniel S. ^{[5
]}

Yang, Yongping ^{[1
]}

Zhou, Tongqing ^{[1
]}

Ahlsen, Goran ^{[6
,7
]}

Bailer, Robert T. ^{[1
]}

Chambers, Michael ^{[1
]}

Chuang, Gwo-Yu ^{[1
]}

Doria-Rose, Nicole A. ^{[1
]}

Druz, Aliaksandr ^{[1
]}

Hallen, Mark A. ^{[1
,8
]}

Harned, Adam ^{[9
]}

Kirys, Tatsiana ^{[1
]}

Louder, Mark K. ^{[1
]}

O'Dell, Sijy ^{[1
]}

Ofek, Gilad ^{[1
]}

Osawa, Keiko ^{[2
]}

Prabhakaran, Madhu ^{[1
]}

Sastry, Mallika ^{[1
]}

Stewart-Jones, Guillaume B. E. ^{[1
]}

Stuckey, Jonathan ^{[1
]}

Thomas, Paul V. ^{[1
]}

Tittley, Tishina ^{[1
]}

Williams, Constance ^{[10
]}

Zhang, Baoshan ^{[1
]}

Zhao, Hong ^{[5
]}

Zhou, Zhou ^{[5
]}

Donald, Bruce R. ^{[9
,11
,12
]}

Lee, Lawrence K.

Zolla-Pazner, Susan ^{[10
,14
]}

Baxa, Ulrich ^{[9
]}

Schoen, Arne ^{[15
]}

Freire, Ernesto ^{[15
]}

Shapiro, Lawrence ^{[1
,6
]}

Lee, Kelly K. ^{[3
,13
]}

Arthos, James ^{[16
]}

Munro, James B. ^{[4
,17
]}

Blanchard, Scott C. ^{[5
]}

Mothes, Walther ^{[4
]}

Binley, James M. ^{[2
]}

机构：

[1] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[2] San Diego Biomed Res Inst, San Diego, CA USA

[3] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA

[4] Yale Univ, Sch Med, Dept Microbial Pathogenesis, New Haven, CT USA

[5] Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA

[6] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA

[7] Columbia Univ, Dept Syst Biol, New York, NY USA

[8] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA

[9] Frederick Natl Lab Canc Res, Leidos Biomed Res, Canc Res Technol Program, Electron Microscopy Lab, Frederick, MD USA

[10] NYU, Sch Med, New York, NY USA

[11] Duke Univ, Dept Chem, Durham, NC 27706 USA

[12] Duke Univ, Dept Comp Sci, Durham, NC 27706 USA

[13] Victor Chang Cardiac Res Inst, Struct & Computat Biol Div, Darlinghurst, NSW, Australia

[14] New York Vet Affairs Harbor Healthcare Syst, New York, NY USA

[15] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA

[16] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA

[17] Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA

来源：

NATURE STRUCTURAL & MOLECULAR BIOLOGY | 2015年 / 22卷 / 07期

基金：

澳大利亚研究理事会; 美国国家卫生研究院; 美国国家科学基金会;

关键词：

IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; ENVELOPE GLYCOPROTEIN COMPLEX; NEUTRALIZING ANTIBODY; FUSION GLYCOPROTEIN; BINDING-SITE; BROAD NEUTRALIZATION; GP120; PROTEIN; EPITOPES;

D O I：

10.1038/nsmb.3051

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

As the sole viral antigen on the HIV-1-virion surface, trimeric Env is a focus of vaccine efforts. Here we present the structure of the ligand-free HIV-1-Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, including a 201C 433C (DS) variant specifically recognized by broadly neutralizing antibodies. DS-Env retained nanomolar affinity for the CD4 receptor, with which it formed an asymmetric intermediate: a closed trimer bound by a single CD4 without the typical antigenic hallmarks of CD4 induction. Antigenicity-guided structural design can thus be used both to delineate mechanism and to fix conformation, with DS-Env trimers in virus-like-particle and soluble formats providing a new generation of vaccine antigens.

引用

页码：522 / +

页数：13

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