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

共 50 条

[1] MAJOR GLYCOPROTEIN ANTIGENS THAT INDUCE ANTIBODIES IN AIDS PATIENTS ARE ENCODED BY HTLV-III
ALLAN, JS
COLIGAN, JE
BARIN, F
MCLANE, MF
SODROSKI, JG
ROSEN, CA
HASELTINE, WA
LEE, TH
ESSEX, M
[J]. SCIENCE, 1985, 228 (4703) : 1091 - 1094
[2] Core structure of gp41 from the HIV envelope glycoprotein
Chan, DC
Fass, D
Berger, JM
Kim, PS
[J]. CELL, 1997, 89 (02) : 263 - 273
[3] The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates
Choe, H
Farzan, M
Sun, Y
Sullivan, N
Rollins, B
Ponath, PD
Wu, LJ
Mackay, CR
LaRosa, G
Newman, W
Gerard, N
Gerard, C
Sodroski, J
[J]. CELL, 1996, 85 (07) : 1135 - 1148
[4] THE CD4 (T4) ANTIGEN IS AN ESSENTIAL COMPONENT OF THE RECEPTOR FOR THE AIDS RETROVIRUS
DALGLEISH, AG
BEVERLEY, PCL
CLAPHAM, PR
CRAWFORD, DH
GREAVES, MF
WEISS, RA
[J]. NATURE, 1984, 312 (5996) : 763 - 767
[5] Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops
Do Kwon, Young
Finzi, Andres
Wu, Xueling
Dogo-Isonagie, Cajetan
Lee, Lawrence K.
Moore, Lucas R.
Schmidt, Stephen D.
Stuckey, Jonathan
Yang, Yongping
Zhou, Tongqing
Zhu, Jiang
Vicic, David A.
Debnath, Asim K.
Shapiro, Lawrence
Bewley, Carole A.
Mascola, John R.
Sodroski, Joseph G.
Kwong, Peter D.
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (15) : 5663 - 5668
[6] Envelope glycans of immunodeficiency virions are almost entirely oligomannose antigens
Doores, Katie J.
Bonomelli, Camille
Harvey, David J.
Vasiljevic, Snezana
Dwek, Raymond A.
Burton, Dennis R.
Crispin, Max
Scanlan, Christopher N.
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (31) : 13800 - 13805
[7] A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors
Doranz, BJ
Rucker, J
Yi, YJ
Smyth, RJ
Samson, M
Peiper, SC
Parmentier, M
Collman, RG
Doms, RW
[J]. CELL, 1996, 85 (07) : 1149 - 1158
[8] HIV-1 entry into CD4(+) cells is mediated by the chemokine receptor CC-CKR-5
Dragic, T
Litwin, V
Allaway, GP
Martin, SR
Huang, YX
Nagashima, KA
Cayanan, C
Maddon, PJ
Koup, RA
Moore, JP
Paxton, WA
[J]. NATURE, 1996, 381 (6584) : 667 - 673
[9] HIV-1 Entry Cofactor: Functional cDNA Cloing of a Seven-Transmembrane, G protein-Coupled Receptor
Feng, Yu
Broder, Christopher C.
Kennedy, Paul E.
Berger, Edward A.
[J]. JOURNAL OF IMMUNOLOGY, 2011, 186 (11) : 872 - 877
[10] Topological Layers in the HIV-1 gp120 Inner Domain Regulate gp41 Interaction and CD4-Triggered Conformational Transitions
Finzi, Andres
Xiang, Shi-Hua
Pacheco, Beatriz
Wang, Liping
Haight, Jessica
Kassa, Aemro
Danek, Brenda
Pancera, Marie
Kwong, Peter D.
Sodroski, Joseph
[J]. MOLECULAR CELL, 2010, 37 (05) : 656 - 667

← 1 2 3 4 5 →