The β20-β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions

被引：81

作者：

Herschhorn, Alon ^{[1
,2
]}

Gu, Christopher ^{[1
]}

Moraca, Francesca ^{[3
]}

Ma, Xiaochu ^{[4
]}

Farrell, Mark ^{[5
]}

Smith, Amos B., III ^{[5
]}

Pancera, Marie ^{[6
]}

Kwong, Peter D. ^{[6
]}

Schon, Arne ^{[7
]}

Freire, Ernesto ^{[7
]}

Abrams, Cameron ^{[3
]}

Blanchard, Scott C. ^{[8
]}

Mothes, Walther ^{[4
]}

Sodroski, Joseph G. ^{[1
,2
,9
]}

机构：

[1] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA

[2] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA

[3] Drexel Univ, Dept Chem & Biol Engn, Philadelphia, PA 19104 USA

[4] Yale Univ, Sch Med, Dept Microbial Pathogenesis, 333 Cedar St, New Haven, CT 06536 USA

[5] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA

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

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

[8] Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA

[9] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

CRYO-EM STRUCTURE; ENVELOPE GLYCOPROTEIN; CRYSTAL-STRUCTURES; ATOMIC-STRUCTURE; RECEPTOR; ENTRY; INHIBITORS; GP41; BROAD; NEUTRALIZATION;

D O I：

10.1038/s41467-017-01119-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The entry of HIV-1 into target cells is mediated by the viral envelope glycoproteins (Env). Binding to the CD4 receptor triggers a cascade of conformational changes in distant domains that move Env from a functionally "closed" State 1 to more "open" conformations, but the molecular mechanisms underlying allosteric regulation of these transitions are still elusive. Here, we develop chemical probes that block CD4-induced conformational changes in Env and use them to identify a potential control switch for Env structural rearrangements. We identify the gp120 beta 20-beta 21 element as a major regulator of Env transitions. Several amino acid changes in the beta 20-beta 21 base lead to open Env conformations, recapitulating the structural changes induced by CD4 binding. These HIV-1 mutants require less CD4 to infect cells and are relatively resistant to State 1-preferring broadly neutralizing antibodies. These data provide insights into the molecular mechanism and vulnerability of HIV-1 entry.

引用

页数：12

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