9o2q

From Proteopedia

BG505-DS SOSIP in complex with 007 bNAb Fabs - Class 0 (unbound)

Structural highlights

9o2q is a 6 chain structure with sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.9Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q2N0S6_HV1 Envelope glycoprotein gp160: Oligomerizes in the host endoplasmic reticulum into predominantly trimers. In a second time, gp160 transits in the host Golgi, where glycosylation is completed. The precursor is then proteolytically cleaved in the trans-Golgi and thereby activated by cellular furin or furin-like proteases to produce gp120 and gp41.[HAMAP-Rule:MF_04083] Surface protein gp120: Attaches the virus to the host lymphoid cell by binding to the primary receptor CD4. This interaction induces a structural rearrangement creating a high affinity binding site for a chemokine coreceptor like CXCR4 and/or CCR5. Acts as a ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on endothelial cells of liver sinusoids and lymph node sinuses. These interactions allow capture of viral particles at mucosal surfaces by these cells and subsequent transmission to permissive cells. HIV subverts the migration properties of dendritic cells to gain access to CD4+ T-cells in lymph nodes. Virus transmission to permissive T-cells occurs either in trans (without DCs infection, through viral capture and transmission), or in cis (following DCs productive infection, through the usual CD4-gp120 interaction), thereby inducing a robust infection. In trans infection, bound virions remain infectious over days and it is proposed that they are not degraded, but protected in non-lysosomal acidic organelles within the DCs close to the cell membrane thus contributing to the viral infectious potential during DCs' migration from the periphery to the lymphoid tissues. On arrival at lymphoid tissues, intact virions recycle back to DCs' cell surface allowing virus transmission to CD4+ T-cells.[HAMAP-Rule:MF_04083] Transmembrane protein gp41: Acts as a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During fusion of viral and target intracellular membranes, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Complete fusion occurs in host cell endosomes and is dynamin-dependent, however some lipid transfer might occur at the plasma membrane. The virus undergoes clathrin-dependent internalization long before endosomal fusion, thus minimizing the surface exposure of conserved viral epitopes during fusion and reducing the efficacy of inhibitors targeting these epitopes. Membranes fusion leads to delivery of the nucleocapsid into the cytoplasm.[HAMAP-Rule:MF_04083]

Publication Abstract from PubMed

Broadly neutralizing antibodies (bNAbs) against HIV-1 can suppress viremia in vivo and inform vaccine development. Here, we characterized 007, a V3 glycan site bNAb exhibiting high levels of antiviral activity against multiclade pseudovirus panels(1-3) (GeoMean IC(50) = 0.012 mug/mL, breadth = 69%, 217 virus strains) by targeting a N332(gp120) glycan-independent V3 epitope, a site of Env vulnerability to which only weakly neutralizing antibodies had previously been identified. Functional analyses demonstrated distinct binding and neutralization profiles compared to classical V3 glycan site bNAbs. A 007 Fab-Env cryo-EM structure revealed contacts with the V3 (324)GD/NIR(327) motif and interactions with N156(gp120) and N301(gp120) glycans. In contrast to classical V3 bNAbs, 007 binding to Env does not depend on the N332(gp120) glycan, rendering it resistant to common escape mutations. Structures of 007 IgG-Env trimer complexes showed two Env trimers crosslinked by three bivalent IgGs, and bivalent 007 IgG was up to ~300-fold more potent than monovalent 007 IgG heterodimer, suggesting a role for avidity in potent neutralization. Finally, in HIV-1(ADA)-infected humanized mice, 007 caused transient decline of viremia and overcame classical V3 escape mutations, highlighting 007's potential for HIV-1 prevention, therapy, functional cure, and vaccine design.

Identification of a broad and potent V3 glycan site bNAb targeting an N332(gp120) glycan-independent epitope.,Gieselmann L, DeLaitsch AT, Rohde M, Radford C, Worczinski J, Momot A, Ahmadov E, Burger JA, Havenar-Daughton C, Deshpande S, Giovannoni F, Corti D, Kreer C, Ercanoglu MS, Schommers P, Georgiev IS, West AP Jr, Knufer J, Stumpf R, Kroidl A, Geldmacher C, Maganga L, William W, Ntinginya NE, Hoelscher M, Yang Z, Wei Q, Renfrow M, Green TJ, Novak J, van Gils MJ, Gristick HB, Gruell H, Bloom JD, Seaman MS, Bjorkman PJ, Klein F bioRxiv [Preprint]. 2025 Sep 10:2025.09.05.674437. doi: , 10.1101/2025.09.05.674437. PMID:40964353^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Gieselmann L, DeLaitsch AT, Rohde M, Radford C, Worczinski J, Momot A, Ahmadov E, Burger JA, Havenar-Daughton C, Deshpande S, Giovannoni F, Corti D, Kreer C, Ercanoglu MS, Schommers P, Georgiev IS, West AP Jr, Knüfer J, Stumpf R, Kroidl A, Geldmacher C, Maganga L, William W, Ntinginya NE, Hoelscher M, Yang Z, Wei Q, Renfrow M, Green TJ, Novak J, van Gils MJ, Gristick HB, Gruell H, Bloom JD, Seaman MS, Bjorkman PJ, Klein F. Identification of a broad and potent V3 glycan site bNAb targeting an N332(gp120) glycan-independent epitope. bioRxiv [Preprint]. 2025 Sep 10:2025.09.05.674437. PMID:40964353 doi:10.1101/2025.09.05.674437