Glycine Substitution at Helix-to-Coil Transitions Facilitates the Structural Determination of a Stabilized Subtype C HIV Envelope Glycoprotein

Summary Advances in HIV‐1 envelope glycoprotein (Env) design generate native‐like trimers and high‐resolution clade A, B, and G structures and elicit neutralizing antibodies. However, a high‐resolution clade C structure is critical, as this subtype accounts for the majority of HIV infections worldwide, but well‐ordered clade C Env trimers are more challenging to produce due to their instability. Based on targeted glycine substitutions in the Env fusion machinery, we defined a general approach that disfavors helical transitions leading to post‐fusion conformations, thereby favoring the pre‐fusion state. We generated a stabilized, soluble clade C Env (16055 NFL) and determined its crystal structure at 3.9 Å. Its overall conformation is similar to SOSIP.664 and native Env trimers but includes a covalent linker between gp120 and gp41, an engineered 201‐433 disulfide bond, and density corresponding to 22 N‐glycans. Env‐structure‐guided design strategies resulted in multiple homogeneous cross‐clade immunogens with the potential to advance HIV vaccine development. Graphical Abstract Figure. No Caption available. HighlightsStructure‐guided design generates an HIV clade C Env crystal structure at 3.9 ÅCross‐clade Env comparison discloses overall structural and N‐glycan conservationThe NFL structure reveals stabilizing TD contacts and the 201C‐A433C disulfide CCNFL Env redesign permits the generation of immunogens derived from clades A, B, and C &NA; The majority of HIV‐1 infections worldwide emanate from subtype C strains. Guenaga et al. describe the 3.9 Å crystal structure of a stabilized subtype C native, flexibly linked (NFL) Env and multiple structure‐guided design strategies that permit the generation of Env immunogens from diverse HIV strains.

• Publication year

  2017

• Venue

  Immunity

• Publication date

  2017-05-16

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.immuni.2017.04.014PMID 28514686PMCID 5439057
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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