Structural basis for llama nanobody recognition and neutralization of HIV-1 at the CD4-binding site.
CD4-binding site
HIV
cryo-EM
crystal structure
envelope trimer
llama VHH
nanobody
neutralization
single-domain antibody
steric clash
Journal
Structure (London, England : 1993)
ISSN: 1878-4186
Titre abrégé: Structure
Pays: United States
ID NLM: 101087697
Informations de publication
Date de publication:
02 06 2022
02 06 2022
Historique:
received:
24
08
2021
revised:
15
12
2021
accepted:
17
03
2022
pubmed:
13
4
2022
medline:
9
6
2022
entrez:
12
4
2022
Statut:
ppublish
Résumé
Nanobodies can achieve remarkable neutralization of genetically diverse pathogens, including HIV-1. To gain insight into their recognition, we determined crystal structures of four llama nanobodies (J3, A12, C8, and D7), all of which targeted the CD4-binding site, in complex with the HIV-1 envelope (Env) gp120 core, and determined a cryoelectron microscopy (cryo-EM) structure of J3 with the Env trimer. Crystal and cryo-EM structures of J3 complexes revealed this nanobody to mimic binding to the prefusion-closed trimer for the primary site of CD4 recognition as well as a secondary quaternary site. In contrast, crystal structures of A12, C8, and D7 with gp120 revealed epitopes that included portions of the gp120 inner domain, inaccessible on the prefusion-closed trimer. Overall, these structures explain the broad and potent neutralization of J3 and limited neutralization of A12, C8, and D7, which utilized binding modes incompatible with the neutralization-targeted prefusion-closed conformation of Env.
Identifiants
pubmed: 35413243
pii: S0969-2126(22)00093-4
doi: 10.1016/j.str.2022.03.012
pmc: PMC9177634
mid: NIHMS1796875
pii:
doi:
Substances chimiques
Antibodies, Neutralizing
0
CD4 Antigens
0
HIV Antibodies
0
HIV Envelope Protein gp120
0
Single-Domain Antibodies
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
862-875.e4Subventions
Organisme : Intramural NIH HHS
ID : ZIA AI005022
Pays : United States
Informations de copyright
Published by Elsevier Ltd.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interest.
Références
J Biol Chem. 2010 Jun 18;285(25):19116-24
pubmed: 20400507
J Comput Chem. 2004 Oct;25(13):1605-12
pubmed: 15264254
Nature. 2002 Dec 12;420(6916):678-82
pubmed: 12478295
J Immunol Methods. 2014 Jul;409:131-46
pubmed: 24291345
Nature. 2021 Jul;595(7866):278-282
pubmed: 34098567
Science. 2011 Dec 2;334(6060):1289-93
pubmed: 22033520
J Exp Med. 2012 Jun 4;209(6):1091-103
pubmed: 22641382
Science. 2010 Aug 13;329(5993):811-7
pubmed: 20616231
Protein Sci. 2018 Jan;27(1):293-315
pubmed: 29067766
Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
pubmed: 15299374
Nature. 2017 Aug 3;548(7665):108-111
pubmed: 28726771
J Struct Biol. 2010 Mar;169(3):389-98
pubmed: 20018246
Nature. 1993 Jun 3;363(6428):446-8
pubmed: 8502296
Vaccines (Basel). 2019 Jul 31;7(3):
pubmed: 31370301
Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W615-9
pubmed: 15215462
J Struct Biol. 2009 Apr;166(1):95-102
pubmed: 19263523
Nat Struct Mol Biol. 2015 Nov;22(11):833-4
pubmed: 26581513
Nat Methods. 2017 Mar;14(3):290-296
pubmed: 28165473
J Struct Biol. 2016 Jan;193(1):1-12
pubmed: 26592709
J Struct Biol. 2015 Nov;192(2):216-21
pubmed: 26278980
MAbs. 2021 Jan-Dec;13(1):1946918
pubmed: 34328065
PLoS One. 2012;7(3):e33298
pubmed: 22438910
Science. 2011 Sep 16;333(6049):1593-602
pubmed: 21835983
Methods Enzymol. 1997;276:307-26
pubmed: 27754618
Cell. 2015 Jun 4;161(6):1280-92
pubmed: 26004070
Nat Methods. 2015 Oct;12(10):943-6
pubmed: 26280328
Vaccine. 2021 Jun 8;39(25):3379-3387
pubmed: 34020817
Nature. 1990 Nov 29;348(6300):411-8
pubmed: 1701030
AIDS Res Hum Retroviruses. 2004 Nov;20(11):1254-8
pubmed: 15588347
Syst Biol. 2012 Dec 1;61(6):1061-7
pubmed: 22780991
Cell. 2016 May 5;165(4):813-26
pubmed: 27114034
PLoS One. 2010 May 05;5(5):e10482
pubmed: 20463957
Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5663-8
pubmed: 22451932
Nature. 2017 Jul 20;547(7663):360-363
pubmed: 28700571
Science. 2015 Jul 10;349(6244):aac4223
pubmed: 26089353
Cell Rep. 2021 Nov 2;37(5):109922
pubmed: 34731616
Nat Struct Mol Biol. 2017 Apr;24(4):370-378
pubmed: 28218750
Nature. 1998 Jun 18;393(6686):648-59
pubmed: 9641677
Science. 2021 Feb 12;371(6530):
pubmed: 33436526
Nature. 2007 Feb 15;445(7129):732-7
pubmed: 17301785
Protein Sci. 2021 Jan;30(1):70-82
pubmed: 32881101
PLoS One. 2019 Apr 17;14(4):e0215163
pubmed: 30995238
J Virol. 1993 Jul;67(7):3978-88
pubmed: 7685405
J Virol. 2008 Dec;82(24):12069-81
pubmed: 18842738
PLoS Pathog. 2014 Dec 18;10(12):e1004552
pubmed: 25522326
J Acquir Immune Defic Syndr (1988). 1993 Jan;6(1):7-14
pubmed: 8417177
J Mol Biol. 2007 Sep 21;372(3):774-97
pubmed: 17681537
Science. 2018 Nov 2;362(6414):598-602
pubmed: 30385580
Science. 2016 Mar 4;351(6277):1043-8
pubmed: 26941313
Immunity. 2016 Nov 15;45(5):1108-1121
pubmed: 27851912
Science. 2000 Mar 3;287(5458):1664-6
pubmed: 10698744
Vaccine. 2007 Sep 28;25(39-40):6852-62
pubmed: 17719149
Nat Struct Mol Biol. 2015 Jul;22(7):522-31
pubmed: 26098315
Vaccine. 2011 Sep 9;29(39):6736-41
pubmed: 21216319
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
pubmed: 15572765
Structure. 2019 Jan 2;27(1):196-206.e6
pubmed: 30471922
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
pubmed: 20124702
Nucleic Acids Res. 2019 Jul 2;47(W1):W636-W641
pubmed: 30976793
Immunity. 2019 Jan 15;50(1):241-252.e6
pubmed: 30552025
BMC Bioinformatics. 2004 Jun 04;5:69
pubmed: 15180909
J Struct Biol. 2005 Jul;151(1):41-60
pubmed: 15890530
Nat Methods. 2017 Apr;14(4):331-332
pubmed: 28250466
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
pubmed: 19461840
Adv Immunol. 2018;137:135-164
pubmed: 29455846
Cell. 2019 Jul 25;178(3):567-584.e19
pubmed: 31348886
Science. 2013 May 10;340(6133):751-6
pubmed: 23661761
Science. 2009 Nov 20;326(5956):1123-7
pubmed: 19965434
Nature. 1990 Nov 29;348(6300):419-26
pubmed: 2247146
J Synchrotron Radiat. 2004 Jan 1;11(Pt 1):53-5
pubmed: 14646133
Science. 2010 Aug 13;329(5993):856-61
pubmed: 20616233
Cell. 2020 Jun 11;181(6):1436-1441
pubmed: 32531248
J Struct Biol. 2012 Dec;180(3):519-30
pubmed: 23000701