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TitleAn MPER antibody neutralizes HIV-1 using germline features shared among donors.
Journal, issue, pagesNat Commun, Vol. 10, Issue 1, Page 5389, Year 2019
Publish dateNov 26, 2019
AuthorsLei Zhang / Adriana Irimia / Lingling He / Elise Landais / Kimmo Rantalainen / Daniel P Leaman / Thomas Vollbrecht / Armando Stano / Daniel I Sands / Arthur S Kim / / Pascal Poignard / Dennis R Burton / Ben Murrell / Andrew B Ward / Jiang Zhu / Ian A Wilson / Michael B Zwick /
PubMed AbstractThe membrane-proximal external region (MPER) of HIV-1 envelope glycoprotein (Env) can be targeted by neutralizing antibodies of exceptional breadth. MPER antibodies usually have long, hydrophobic ...The membrane-proximal external region (MPER) of HIV-1 envelope glycoprotein (Env) can be targeted by neutralizing antibodies of exceptional breadth. MPER antibodies usually have long, hydrophobic CDRH3s, lack activity as inferred germline precursors, are often from the minor IgG3 subclass, and some are polyreactive, such as 4E10. Here we describe an MPER broadly neutralizing antibody from the major IgG1 subclass, PGZL1, which shares germline V/D-region genes with 4E10, has a shorter CDRH3, and is less polyreactive. A recombinant sublineage variant pan-neutralizes a 130-isolate panel at 1.4 μg/ml (IC). Notably, a germline revertant with mature CDR3s neutralizes 12% of viruses and still binds MPER after DJ reversion. Crystal structures of lipid-bound PGZL1 variants and cryo-EM reconstruction of an Env-PGZL1 complex reveal how these antibodies recognize MPER and viral membrane. Discovery of common genetic and structural elements among MPER antibodies from different patients suggests that such antibodies could be elicited using carefully designed immunogens.
External linksNat Commun / PubMed:31772165 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.402 - 8.9 Å
Structure data

EMDB-0620:
Full length HIV-1 Envelope glycoprotein clone AMC011 in complex with PGT151 Fab and PGZL1 Fab
Method: EM (single particle) / Resolution: 8.9 Å

PDB-6o3d:
Crystal structure of the unbound Fab fragment of the human HIV-1 neutralizing antibody PGZL1.
Method: X-RAY DIFFRACTION / Resolution: 1.402 Å

PDB-6o3g:
Crystal structure of the Fab fragment of the human HIV-1 neutralizing antibody PGZL1 in complex with its MPER peptide epitope (region 671-683 of HIV-1 gp41).
Method: X-RAY DIFFRACTION / Resolution: 3.645 Å

PDB-6o3j:
Crystal structure of the Fab fragment of the human HIV-1 neutralizing antibody PGZL1 in complex with its MPER peptide epitope (region 671-683 of HIV-1 gp41) and phosphatidic acid (06:0 PA)
Method: X-RAY DIFFRACTION / Resolution: 3.416 Å

PDB-6o3k:
Crystal structure of the unbound Fab fragment of the human HIV-1 neutralizing antibody PGZL1.H4K3
Method: X-RAY DIFFRACTION / Resolution: 1.451 Å

PDB-6o3l:
Crystal structure of the Fab fragment of the human HIV-1 neutralizing antibody PGZL1.H4K3 in complex with its MPER peptide epitope (region 671-683 of HIV-1 gp41).
Method: X-RAY DIFFRACTION / Resolution: 1.98 Å

PDB-6o3u:
Crystal structure of the Fab fragment of the human HIV-1 neutralizing antibody PGZL1.H4K3 in complex with 06:0 PA
Method: X-RAY DIFFRACTION / Resolution: 3.105 Å

PDB-6o41:
Crystal structure of the unbound PGZL1 germline Fab fragment (PGZL1_gVmDmJ)
Method: X-RAY DIFFRACTION / Resolution: 2.465 Å

PDB-6o42:
Crystal structure of the germline PGZL1 (PGZL1_gVmDmJ) Fab in complex with MPER peptide epitope.
Method: X-RAY DIFFRACTION / Resolution: 2.6 Å

Chemicals

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-SO4:
SULFATE ION / Sulfate

ChemComp-HOH:
WATER / Water

ChemComp-44E:
(2R)-3-(phosphonooxy)propane-1,2-diyl dihexanoate / phospholipid*YM

ChemComp-MPD:
(4S)-2-METHYL-2,4-PENTANEDIOL / precipitant*YM / 2-Methyl-2,4-pentanediol

ChemComp-PO4:
PHOSPHATE ION / Phosphate

Source
  • homo sapiens (human)
  • human immunodeficiency virus 1
  • streptococcus sp. group g (bacteria)
KeywordsIMMUNE SYSTEM / PGZL1 ANTI HIV-1 / GP41 MPER / MEMBRANE LIPIDS / BROADLY NEUTRALISING HIV-1 ANTIBODY / PGZL1.H4K3 ANTI HIV-1 / germline PGZL1 ANTI HIV-1

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