9Z0S

Fab/epitope complex structure of anti-Tau monoclonal antibody PHF-1

Summary for 9Z0S

• Entry DOI: 10.2210/pdb9z0s/pdb
• Descriptor: Light chain of Fab fragment of anti-Tau mAb PHF-1, Heavy chain of Fab fragment of anti-Tau mAb PHF-1, Microtubule-associated protein tau, ... (4 entities in total)
• Functional Keywords: anti-tau monoclonal antibody, neuropeptide-immune system complex, neuropeptide/immune system
• Biological source: Mus musculus (mouse); More
• Total number of polymer chains: 18
• Total formula weight: 302041.54

Authors

Pan, R.,Kong, X.P. (deposition date: 2025-11-03, release date: 2026-10-14, Last modification date: 2026-10-21)

Primary citation

Pan, R.,Congdon, E.E.,Chukwu, J.E.,Luo, C.C.,Sigurdsson, E.M.,Kong, X.P.
Tau pSer396 and pSer404 Define Distinct Epitope Regions Linked to Different Antibody Functions.
Biorxiv, 2026

PubMed Abstract: Hyperphosphorylated tau is a central pathological feature of Alzheimer's disease and related tauopathies, and antibodies targeting the pSer396/pSer404 epitope region represent a promising therapeutic strategy. However, direct comparisons of pSer396- and pSer404-selective antibodies and the impact of humanization on their functional properties remain limited. We generated two new monoclonal antibodies (mAbs), 9E (pSer404-specific) and G10 (pSer396-specific), and evaluated them alongside 4E6 (pSer404) and PHF-1 (pSer396) in murine and partially humanized chimeric formats. Antibodies were assessed in mixed cortical cultures using extracellular (PHF + Ab) and intracellular (PHF → Ab) paradigms. Efficacy in preventing tau-induced toxicity and seeding differed substantially among antibodies and was variably altered by chimerization, despite identical variable regions. Antibodies targeting pSer404 were more effective than those targeting pSer396, and antibodies that preferentially bound soluble pathological tau species in competition ELISA were consistently more efficacious, whereas neuronal uptake was comparable across variants. To define structural determinants of phospho-epitope recognition, we determined the crystal structures of the Fab regions of 9E, G10, and PHF-1, and additionally solved the co-crystal structure of Fab PHF-1 in complex with a pSer396 tau peptide at 2.55 Å resolution. The PHF-1 complex reveals a heavy-chain-dominant binding mode in which pSer396 is anchored within an electropositive pocket and Tyr394 adopts a flipped conformation that stabilizes a β-strand-like motif, consistent with a phosphorylation-dependent conformational switch. These findings demonstrate that epitope selectivity, aggregate preference, structural binding mode, and Fc context collectively govern antibody efficacy, and that humanization can substantially alter therapeutic properties.

PubMed: 42079100
DOI: 10.64898/2026.04.16.716390

Experimental method

X-RAY DIFFRACTION (2.55 Å)