Thanks to all the Klein lab in Cologne and the many other collaborators who contributed to this work!
03.02.2026 19:04
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Thanks to all the Klein lab in Cologne and the many other collaborators who contributed to this work!
We then probed the mechanism(s): modeling intra-spike crosslinking on open Env conformations, and observing 007 IgG-crosslinked "trimer dimers" in solution, structures that could drive viral aggregation.
Ultimately, however, we could only speculate what was happening in neutralization assays. (4/5)
This led us to revisit neutralization assays.
Comparing bivalent 007 (IgG1, IgG3) with monovalent forms revealed a key insight:
bivalency plays a central role in 007's neutralization mechanism - surprising, given the HIV bNAbs by and large do not rely on avidity. (3/5)
Cryo-EM gave us the first clue that this bNAb Fab exhibited weak affinity for the BG505 Env trimer, despite being remarkably potent against BG505
SPR confirmed this: ~5uM affinity for the Fab
Confusing... given how potent 007 is π€ (2/5)
bNAb #007.
#HIV #antibody #V3 #avidity #cryo-EM
www.nature.com/articles/s41...
Cryo-EM revealed trimers with 0, 1, 2, or 3 Fabs bound -leading to some surprising insights into avidity and neutralization that make 007 stand out for more than just its name. (1/5)
Was such a great class last year! Iβd highly recommend to ppl getting into tomography
Workflow Using a Cryogenic Coincident Fluorescence, Electron, and Ion Beam Microscope for Targeted Milling of Cells pubmed.ncbi.nlm.nih.gov/41182991/ #cryoEM
Thank you!
Huge thanks to Florian Klein's lab for this excellent collaboration and to the various lab members who provided so much help seeing this through!
All these antibodies exhibit canonical gp120 interactions made by CD4 and CD4bs bNAbs. Interestingly, the VH1-2-encoded N58 is mutated to K58 in the best of these bNAbs, which mimics interactions made between K35 of CD4 and gp120. www.nature.com/articles/s41...
The third bNAb, 05_B08, does not have any insertions and does not contact the adjacent gp120. This antibody, exhibited just over 50% breadth, which is much lower than the others.
Another of the bNAbs, 01_D03, has two separate insertions and a 20-residue long CDRH3, which together allow it to contact conserved residues on the adjacent gp120. This antibody has a 4-residue long FWRH3 insertion in the same location as a 4-residue insertion in 3BNC60/3BNC117.
Interestingly, a crystal structure of this antibody alone revealed this protruding loop was pre-organized for binding, which is expected to lower the entropic cost for binding.
These bNAbs differ in the length and position of insertions. The best-in-class bNAb, 04_A06, has an 11-residue long FWRH1 insertion which manifests in a long CDRH1 that reaches over to contact highly conserved residues on the adjacent gp120.
a, Schematics illustrating the position and length of FWRH1 and/or FWRH3 insertions of 04_A06 (left), 01_D03 (middle) and 05_B08 (right; top), EM maps showing side views of 04_A06, 01_D03 and 05_B08 bnAb Fabs in complex with BG505SOSIP.664 Env trimers (middle) and insets illustrating a close-up of bnAb interactions with the adjacent gp120 protomer (gp1202; bottom); HC, heavy chain; LC, light chain. b, Canonical interactions of CD4 and bnAbs to the CD4bs (04_A06, IOMA and VRC01) with Env gp120 D368, the F43 pocket and gp120 N280/R456. c, Interactions between the CDRH1s of 04_A06 (blue cartoon representation) and 1-18 (red cartoon representation) with the secondary (gp1202) Env protomer, shown as a surface colored by percent conservation. The inset (top right) shows the Env trimerβ04_A06 complex as a surface representation for orientation. d, Crystal structure of unbound 04_A06 Fab (bottom) and inset highlighting the 04_A06 CDRH1, with electron density contoured at 1.5Ο (top). e, Molecular surface representation showing the surface area buried by VRC01-class bnAbs (04_A06, 01_D03, 05_08, 3BNC117 and VRC01) on primary (gp1201) or secondary (gp1202) Env protomers (top). Listing of Protein Data Bank (PDB) accession codes, breadth (%), heavy chain insertion length and position, buried surface area (BSA) on gp1201 and gp1202 as well as total BSA for VRC01-class bnAbs (bottom).
There's a new best-in-class HIV-1 antibody out today! Happy to have contributed to the structural characterization of this, and two other distinct VRC01-class bNAbs isolated from a single individual. www.nature.com/articles/s41...
I second this bet.
And then Shankar Balasubramanian for chemistry.
From what I gather, CXCR4 (previously called fusin) was identified as a co-receptor for HIV nearly 30 years ago (pubmed.ncbi.nlm.nih.gov/8629022/). Nice to see a structure, and interesting to see it was done with HIV-2 gp120.
I am excited to share our new preprint on the CAGE complex, a mysterious hollow protein complex that I first saw years ago while surveying Tetrahymena ciliary lysate www.biorxiv.org/content/10.1... #cilia #protistsonsky π§¬π§ͺ
Super cool!
π£ New paper alert! Just out in Cell Reports! pubmed.ncbi.nlm.nih.gov/40644298/
Thrilled to share that we have discovered a brand-new anti-phage defense system! Bacteria have evolved various defense strategies (CRISPR etc) to counter phage attacks. We found a new one - fascinating and dramatic
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βOn Being The Right Sizeβ is a true classic, highly recommend! www.phys.ufl.edu/courses/phy3...
If Management is the Only Way Up, We're All F'd - Rand Fishkin
sparktoro.com/blog/if-mana...
Latest preprint from the lab, many years in the making!
By combining #cryoEM with #AlphaFold3 modelling, we propose that norovirus NS3 forms a transmembrane RNA translocase.
This could have big implications for our understanding of viral replication & assembly (π§΅)
www.biorxiv.org/content/10.1...
Cool structure!
Cool demo! Also, itβs nice to see your IgG binds bivalently!
Instant classic π€―
My first project in the @elowitzlab.bsky.social is finally out in @cellpress.bsky.social! We explore how competitive, "many-to-many" dimerization allows complex, multi-input, and cell-type-specific biochemical computationsπ§΅β
doi.org/10.1016/j.ce...
MISO: Microfluidic protein isolation enables single particle cryo-EM structure determination from a single cell colony https://www.biorxiv.org/content/10.1101/2025.01.10.632437v1
