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TitleConformational Plasticity in the HIV-1 Fusion Peptide Facilitates Recognition by Broadly Neutralizing Antibodies.
Journal, issue, pagesCell Host Microbe, Vol. 25, Issue 6, Page 873-883.e5, Year 2019
Publish dateJun 12, 2019
AuthorsMeng Yuan / Christopher A Cottrell / Gabriel Ozorowski / Marit J van Gils / Sonu Kumar / Nicholas C Wu / Anita Sarkar / Jonathan L Torres / Natalia de Val / Jeffrey Copps / John P Moore / Rogier W Sanders / Andrew B Ward / Ian A Wilson /
PubMed AbstractThe fusion peptide (FP) of HIV-1 envelope glycoprotein (Env) is essential for mediating viral entry. Detection of broadly neutralizing antibodies (bnAbs) that interact with the FP has revealed it as ...The fusion peptide (FP) of HIV-1 envelope glycoprotein (Env) is essential for mediating viral entry. Detection of broadly neutralizing antibodies (bnAbs) that interact with the FP has revealed it as a site of vulnerability. We delineate X-ray and cryo-electron microscopy (cryo-EM) structures of bnAb ACS202, from an HIV-infected elite neutralizer, with an FP and with a soluble Env trimer (AMC011 SOSIP.v4.2) derived from the same patient. We show that ACS202 CDRH3 forms a "β strand" interaction with the exposed hydrophobic FP and recognizes a continuous region of gp120, including a conserved N-linked glycan at N88. A cryo-EM structure of another previously identified bnAb VRC34.01 with AMC011 SOSIP.v4.2 shows that it also penetrates through glycans to target the FP. We further demonstrate that the FP can twist and present different conformations for recognition by bnAbs, which enables approach to Env from diverse angles. The variable recognition of FP by bnAbs thus provides insights for vaccine design.
External linksCell Host Microbe / PubMed:31194940 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.76 - 5.2 Å
Structure data

0433

6nc2

EMDB-0433, PDB-6nc2:
AMC011 v4.2 SOSIP Env trimer in complex with fusion peptide targeting antibody ACS202 fragment antigen binding
Method: EM (single particle) / Resolution: 5.2 Å

0434

6nc3

EMDB-0434, PDB-6nc3:
AMC011 v4.2 SOSIP Env trimer in complex with fusion peptide targeting antibody VRC34 fragment antigen binding
Method: EM (single particle) / Resolution: 4.5 Å

PDB-6ncp:
Crystal structure of HIV-1 broadly neutralizing antibody ACS202
Method: X-RAY DIFFRACTION / Resolution: 2.76 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-SO4:
SULFATE ION / Sulfate

ChemComp-GLY:
GLYCINE / Glycine

ChemComp-HOH:
WATER / Water

Source
  • human immunodeficiency virus 1
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsIMMUNE SYSTEM / HIV-1 Env / SOSIP / trimer / broadly neutralizing antibody / fusion peptide / VIRAL PROTEIN / antibody / HIV / envelope glycoprotein

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