9MSP

Crystal structure of MPXV A35R in complex with neutralizing antibody EV35-7

Summary for 9MSP

• Entry DOI: 10.2210/pdb9msp/pdb
• Descriptor: Protein OPG161, EV35-7 heavy chain, EV35-7 light chain, ... (7 entities in total)
• Functional Keywords: antibody, mpox, monkeypox, a35, immune system
• Biological source: Monkeypox virus; More
• Total number of polymer chains: 8
• Total formula weight: 140667.75

Authors

Yuan, M.,Wilson, I.A. (deposition date: 2025-01-10, release date: 2025-09-10)

Primary citation

Fantin, R.F.,Yuan, M.,Park, S.C.,Bozarth, B.,Cohn, H.,Ignacio, M.,Earl, P.,Civljak, A.,Laghlali, G.,Zhang, D.,Zhu, X.,Crandell, J.,Monteiro, V.,Clark, J.J.,Cotter, C.,Burkhardt, M.,Singh, G.,Warang, P.,Garcia-Bernalt Diego, J.,Srivastava, K.,Lugo, L.A.,Pischel, L.,Yildirim, I.,Omer, S.B.,da Silva, D.,Krammer, F.,Bajic, G.,Simon, V.,Schotsaert, M.,Lucas, C.,Wilson, I.A.,Moss, B.,Coelho, C.H.
Human monoclonal antibodies targeting A35 protect from death caused by mpox.
Cell, 2025

PubMed Abstract: The 2022 mpox outbreak highlighted the serious threat of monkeypox virus (MPXV), yet effective treatments are lacking. From an mpox-convalescent individual, we identified three high-affinity human monoclonal antibodies (mAbs) (named EV35-2, EV35-6, and EV35-7) that target the A35 protein in MPXV. These antibodies block viral spread in vitro and protect mice against lethal MPXV and vaccinia virus infection via both Fc-dependent and independent mechanisms. Levels of serum antibodies targeting the same epitopes are increased in mpox-convalescent humans, and higher levels of these antibodies in the sera are linked to shorter symptom duration and no hospitalization. Systems-level multivariate analysis indicated that mpox-convalescent serum antibodies targeting the same epitopic region as these three mAbs may function cooperatively, with additive associations to clinical protection. Two of the antibodies use a conserved IGHD2-21-encoded CxGGDCx motif in their CDRH3 region to bind a highly conserved poxvirus epitope. These findings establish A35 as a critical therapeutic target and highlight A35-specific mAbs as promising candidates for next-generation orthopoxvirus treatments.

PubMed: 40865529
DOI: 10.1016/j.cell.2025.08.004

Experimental method

X-RAY DIFFRACTION (2.19 Å)